Compounds for treating spinal muscular atrophy

ABSTRACT

The present invention provides compounds of formula (I) wherein A, B, X, Y, R1 and R2 are as described herein, as well as pharmaceutically acceptable salts thereof. Further the present invention is concerned with the manufacture of the compounds of formula (I), pharmaceutical compositions comprising them and their use as medicaments.

INTRODUCTION

The present invention provides compounds which are SMN2 gene splicingmodulators, their manufacture, pharmaceutical compositions comprisingthem and their use as medicaments for the treatment of spinal muscularatrophy (SMA).

In particular, the present invention relates to compounds of formula (I)

wherein A, B, X, Y, R¹ and R² are as described herein, andpharmaceutically acceptable salts thereof.

BACKGROUND

Spinal muscular atrophy (SMA), in its broadest sense, describes acollection of inherited and acquired central nervous system (CNS)diseases characterized by progressive motor neuron loss in the spinalcord and brainstem causing muscle weakness and muscle atrophy. The mostcommon form of SMA is caused by mutations in the Survival Motor Neuron(SMN) gene and manifests over a wide range of severity affecting infantsthrough adults (Crawford and Pardo, Neurobiol. Dis., 1996, 3:97).

Infantile SMA is the most severe form of this neurodegenerativedisorder. Symptoms include muscle weakness, poor muscle tone, weak cry,limpness or a tendency to flop, difficulty sucking or swallowing,accumulation of secretions in the lungs or throat, feeding difficulties,and increased susceptibility to respiratory tract infections. The legstend to be weaker than the arms and developmental milestones, such aslifting the head or sitting up, cannot be reached. In general, theearlier the symptoms appear, the shorter the lifespan. As the motorneuron cells deteriorate, symptoms appear shortly afterward. The severeforms of the disease are fatal and all forms have no known cure. Thecourse of SMA is directly related to the rate of motor neuron celldeterioration and the resulting severity of weakness. Infants with asevere form of SMA frequently succumb to respiratory disease due toweakness in the muscles that support breathing. Children with milderforms of SMA live much longer, although they may need extensive medicalsupport, especially those at the more severe end of the spectrum. Theclinical spectrum of SMA disorders has been divided into the followingfive groups.

-   -   (a) Type 0 SMA (In Utero SMA) is the most severe form of the        disease and begins before birth. Usually, the first symptom of        Type 0 SMA is reduced movement of the fetus that can first be        observed between 30 and 36 weeks of pregnancy. After birth,        these newborns have little movement and have difficulties with        swallowing and breathing.    -   (b) Type 1 SMA (Infantile SMA or Werdnig-Hoffmann disease)        presents symptoms between 0 and 6 months. form of SMA is also        very severe. Patients never achieve the ability to sit, and        death usually occurs within the first 2 years without        ventilatory support.    -   (c) Type 2 SMA (Intermediate SMA) has an age of onset at 7-18        months. Patients achieve the ability to sit unsupported, but        never stand or walk unaided. Prognosis in this group is largely        dependent on the degree of respiratory involvement.    -   (d) Type 3 SMA (Juvenile SMA or Kugelberg-Welander disease) is        generally diagnosed after 18 months. Type 3 SMA individuals are        able to walk independently at some point during their disease        course but often become wheelchair-bound during youth or        adulthood.    -   (e) Type 4 SMA (Adult onset SMA). Weakness usually begins in        late adolescence in the tongue, hands, or feet, then progresses        to other areas of the body. The course of adult SMA is much        slower and has little or no impact on life expectancy.

The SMN gene has been mapped by linkage analysis to a complex region inchromosome 5q. In humans, this region contains an approximately 500thousand base pairs (kb) inverted duplication resulting in two nearlyidentical copies of the SMN gene. SMA is caused by an inactivatingmutation or deletion of the telomeric copy of the gene (SMN1) in bothchromosomes, resulting in the loss of SMN1 gene function. However, allpatients retain the centromeric copy of the gene (SMN2), and the copynumber of the SMN2 gene in SMA patients generally correlates inverselywith the disease severity; i.e., patients with less severe SMA have morecopies of SMN2. Nevertheless, SMN2 is unable to compensate completelyfor the loss of SMN1 function due to alternative splicing of exon 7caused by a translationally silent C to T mutation in exon 7. As aresult, the majority of transcripts produced from SMN2 lack exon 7 (Δ7SMN2), and encode a truncated SMN protein that has an impaired functionand is rapidly degraded.

The SMN protein is thought to play a role in RNA processing andmetabolism, having a well characterized function of mediating theassembly of a specific class of RNA-protein complexes termed snRNPs. SMNmay have other functions in motor neurons, however its role inpreventing the selective degeneration of motor neurons is not wellestablished.

In most cases, SMA is diagnosed based on clinical symptoms and by thepresence of at least one copy of the SMN1 gene test. However, inapproximately 5% of cases SMA is caused by mutation in genes other thanthe inactivation of SMN 1, some known and others not yet defined. Insome cases, when the SMN 1 gene test is not feasible or does not showany abnormality, other tests such as an electromyography (EMG) or musclebiopsy may be indicated.

Medical care for SMA patients at present is limited to supportivetherapy including respiratory, nutritional and rehabilitation care;there is no drug known to address the underlying cause of the disease.Current treatment for SMA consists of prevention and management of thesecondary effects of chronic motor unit loss. The major management issuein Type 1 SMA is the prevention and early treatment of pulmonaryproblems, which are the cause of death in the majority of the cases.While some infants afflicted with SMA grow to be adults, those with Type1 SMA have a life expectancy of less than two years.

Several mouse models of SMA have been developed. In particular, the SMNdelta exon 7 (Δ7 SMN) model (Le et al., Hum. Mol. Genet., 2005, 14:845)carries both the SMN2 gene and several copies of the Δ7 SMN2 cDNA andrecapitulates many of the phenotypic features of Type 1 SMA. The Δ7 SMNmodel can be used for both SMN2 expression studies as well as theevaluation of motor function and survival. The C/C-allele mouse model(Jackson Laboratory strain #008714, The Jackson Laboratory, Bar Harbor,Me.) provides a less severe SMA disease model, with mice having reducedlevels of both SMN2 full length (FL SMN2) mRNA and SMN protein. TheC/C-allele mouse phenotype has the SMN2 gene and a hybrid mSMN1-SMN2gene that undergoes alternative splicing, but does not have overt muscleweakness. The C/C-allele mouse model is used for SMN2 expressionstudies.

As a result of improved understanding of the genetic basis andpathophysiology of SMA, several strategies for treatment have beenexplored, but none have yet demonstrated success in the clinic.

Gene replacement of SMN1, using viral delivery vectors, and cellreplacement, using differentiated SMN1^(+/+) stem cells, havedemonstrated efficacy in animal models of SMA. More research is neededto determine the safety and immune response and to address therequirement for the initiation of treatment at the neonatal stage beforethese approaches can be applied to humans.

Correction of alternative splicing of SMN2 in cultured cells has alsobeen achieved using synthetic nucleic acids as therapeutic agents: (i)antisense oligonucleotides that target sequence elements in SMN2pre-mRNA and shift the outcome of the splicing reaction toward thegeneration of full length SMN2 mRNA (Passini et al., Sci. Transl. Med.,2011, 3:72ra18; and, Hua et al., Nature, 2011, 478:123) and (ii)trans-splicing RNA molecules that provide a fully functional RNAsequence that replace the mutant fragment during splicing and generate afull length SMN1 mRNA (Coady and Lorson, J Neurosci., 2010, 30:126).

Other approaches under exploration include searching for drugs thatincrease SMN levels, enhance residual SMN function, or compensate forits loss. Aminoglycosides have been shown to enhance expression of astabilized SMN protein produced from Δ7 SMN2 mRNA by promoting thetranslational read-through of the aberrant stop codon, but have poorcentral nervous system penetration and are toxic after repeat dosing.Chemotherapeutic agents, such as aclarubicin, have been shown toincrease SMN protein in cell culture; however, the toxicity profile ofthese drugs prohibits long-term use in SMA patients. Some drugs underclinical investigation for the treatment of SMA include transcriptionactivators such as histone deacetylase (“HDAC”) inhibitors (e.g.,butyrates, valproic acid, and hydroxyurea), and mRNA stabilizers (mRNAdecapping inhibitor RG3039 from Repligen), the goal being to increasethe amount of total RNA transcribed from the SMN2 gene. However, the useof the HDAC inhibitors or mRNA stabilizers does not address theunderlying cause of SMA and may result in a global increase intranscription and gene expression with potential safety problems inhumans.

In an alternative approach, neuroprotective agents such as Olesoximehave been chosen for investigation. Such strategies are not aimed at SMNfor the treatment of SMA, but instead are being explored to protect theSMN-deficient motor neurons from neurodegeneration.

A system designed for identifying compounds that increase the inclusionof exon 7 of SMN into RNA transcribed from the SMN2 gene and certainbenzooxazole and benzoisoxazole compounds identified thereby have beendescribed in International Patent Application WO2009/151546A1. A systemdesigned for identifying compounds that cause ribosomal frameshifting toproduce a stabilized SMN protein from Δ7 SMN2 mRNA and certainisoindolinone compounds identified thereby have been described inInternational Patent Application WO2010/019236A1.

Despite the progress made in understanding the genetic basis andpathophysiology of SMA, there remains a need to identify compounds thatalter the course of spinal muscular atrophy, one of the most devastatingchildhood neurological diseases.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the invention, suitable methods and materials aredescribed below.

All publications, patent applications, patents, and other referencesmentioned herein are incorporated by reference in their entirety.

The nomenclature used in this Application is based on IUPAC systematicnomenclature, unless indicated otherwise.

Any open valency appearing on a carbon, oxygen, sulfur or nitrogen atomin the structures herein indicates the presence of a hydrogen, unlessindicated otherwise.

The definitions described herein apply irrespective of whether the termsin question appear alone or in combination. It is contemplated that thedefinitions described herein can be appended to form chemically-relevantcombinations, such as e.g. “heterocycloalkylaryl”,“haloalkylheteroaryl”, “arylalkylheterocycloalkyl”, or “alkoxyalkyl”.The last member of the combination is the radical which is binding tothe rest of the molecule. The other members of the combination areattached to the binding radical in reversed order in respect of theliteral sequence, e.g. the combination arylalkylheterocycloalkyl refersto a heterocycloalkyl-radical which is substituted by an alkyl which issubstituted by an aryl.

The term “moiety” refers to an atom or group of chemically bonded atomsthat is attached to another atom or molecule by one or more chemicalbonds thereby forming part of a molecule. For example, the variables R¹and R² of formula (I) refer to moieties that are attached to the corestructure of formula I by a covalent bond.

When indicating the number of substituents, the term “one or more”refers to the range from one substituent to the highest possible numberof substitution, i.e. replacement of one hydrogen up to replacement ofall hydrogens by substituents.

The term “optional” or “optionally” denotes that a subsequentlydescribed event or circumstance can but need not occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not.

The term “substituent” denotes an atom or a group of atoms replacing ahydrogen atom on the parent molecule.

The term “substituted” denotes that a specified group bears one or moresubstituents. Where any group can carry multiple substituents and avariety of possible substituents is provided, the substituents areindependently selected and need not to be the same. The term“unsubstituted” means that the specified group bears no substituents.The term “optionally substituted” means that the specified group isunsubstituted or substituted by one or more substituents, independentlychosen from the group of possible substituents. When indicating thenumber of substituents, the term “one or more” means from onesubstituent to the highest possible number of substitution, i.e.replacement of one hydrogen up to replacement of all hydrogens bysubstituents.

The term “compound(s) of this invention” and “compound(s) of the presentinvention” refers to compounds of formula (I) as disclosed herein andstereoisomers, tautomers, solvates, and salts (e.g., pharmaceuticallyacceptable salts) thereof.

When the compounds of the invention are solids, it is understood bythose skilled in the art that these compounds, and their solvates andsalts, may exist in different solid forms, particularly differentcrystal forms, all of which are intended to be within the scope of thepresent invention and specified formulas.

The term “pharmaceutically acceptable salts” denotes salts which are notbiologically or otherwise undesirable. Pharmaceutically acceptable saltsinclude both acid and base addition salts.

The term “pharmaceutically acceptable acid addition salt” denotes thosepharmaceutically acceptable salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,carbonic acid, phosphoric acid, and organic acids selected fromaliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic, and sulfonic classes of organic acids such as formic acid,acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid,pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid,succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid,ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamicacid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonicacid, ethanesulfonic acid, p-toluenesulfonic acid, and salicyclic acid.

Particular pharmaceutically acceptable salts of the present inventionare salts formed with hydrochloric acid yielding a hydrochloride,dihydrochloride, or trihydrochloride salt.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. In describing an optically active compound, the prefixes Dand L, or R and S, are used to denote the absolute configuration of themolecule about its chiral center(s). The substituents attached to thechiral center under consideration are ranked in accordance with theSequence Rule of Cahn, Ingold and Prelog. (Cahn et al. Angew. Chem.Inter. Edit. 1966, 5, 385; errata 511). The prefixes D and L or (+) and(−) are employed to designate the sign of rotation of plane-polarizedlight by the compound, with (−) or L designating that the compound islevorotatory. A compound prefixed with (+) or D is dextrorotatory.

The “basicity” of a compound is expressed herein by the negative decadiclogarithm of the acidity constant of the conjugate acid (pKa=−log Ka).The larger the pKa of the conjugate acid, the stronger the base(pKa+pKb=14). In this application, an atom or functional group isdenoted “basic” if it is suitable to accept a proton and if thecalculated pKa of its conjugate acid is at least 7, more particularly ifthe calculated pKa of its conjugate acid is at least 7.8, mostparticularly if the calculated pKa of its conjugate acid is at least 8.pKa values were calculated in-silico as described in F. Milletti et al.,J. Chem. Inf Model (2007) 47:2172-2181.

The term “halo”, “halogen”, and “halide” are used interchangeably hereinand denote fluoro, chloro, bromo, or iodo. Particular examples of haloare fluoro and chloro, most particularly fluoro.

The term “alkyl” denotes a monovalent linear or branched saturatedhydrocarbon group of 1 to 7 carbon atoms. In particular embodiments,alkyl has 1 to 4 carbon atoms, and in more particular embodiments 1 to 2carbon atoms. Examples of alkyl include methyl, ethyl, propyl,isopropyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. Particularexamples of alkyl are methyl and ethyl.

The term “alkoxy” denotes a group of the formula —O—R′, wherein R′ is analkyl group. Examples of alkoxy moieties include methoxy, ethoxy,isopropoxy, and tert-butoxy. Particular examples of alkoxy are methoxyand ethoxy.

The term “haloalkyl” denotes an alkyl group wherein at least one of thehydrogen atoms of the alkyl group has been replaced by same or differenthalogen atoms, particularly fluoro atoms. Examples of haloalkyl includemonofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, forexample 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,fluoromethyl, or trifluoromethyl. The term “perhaloalkyl” denotes analkyl group where all hydrogen atoms of the alkyl group have beenreplaced by the same or different halogen atoms. Particular example ofhaloalkyl is trifluoromethyl.

The term “haloalkoxy” denotes an alkoxy group wherein at least one ofthe hydrogen atoms of the alkoxy group has been replaced by same ordifferent halogen atoms, particularly fluoro atoms. Examples ofhaloalkoxyl include monofluoro-, difluoro- or trifluoro-methoxy, -ethoxyor -propoxy, for example 3,3,3-trifluoropropoxy, 2-fluoroethoxy,2,2,2-trifluoroethoxy, fluoromethoxy, or trifluoromethoxy. The term“perhaloalkoxy” denotes an alkoxy group where all hydrogen atoms of thealkoxy group have been replaced by the same or different halogen atoms.Particular example of haloalkoxy is 2,2,2-trifluoroethoxy.

The term “bicyclic ring system” denotes two rings which are fused toeach other via a common single or double bond (annelated bicyclic ringsystem), via a sequence of three or more common atoms (bridged bicyclicring system) or via a common single atom (spiro bicyclic ring system).Bicyclic ring systems can be saturated, partially unsaturated,unsaturated or aromatic. Bicyclic ring systems can comprise heteroatomsselected from N, O and S.

The term “cycloalkyl” denotes a monovalent saturated monocyclichydrocarbon group of 3 to 7 ring carbon atoms. Examples for cycloalkylare cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl.Particular example for cycloalkyl is cyclopropyl.

The term “heterocycloalkyl” denotes a monovalent saturated or partlyunsaturated mono- or bicyclic ring system of 3 to 9 ring atoms,comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, theremaining ring atoms being carbon. In particular embodiments,heterocycloalkyl is a monovalent saturated monocyclic ring system of 4to 7 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N,O and S, the remaining ring atoms being carbon. Examples for monocyclicsaturated heterocycloalkyl are aziridinyl, oxiranyl, azetidinyl,oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl,pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl,thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl,piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl,azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. Examples forbicyclic saturated heterocycloalkyl are 8-aza-bicyclo[3.2.1]octyl,quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl,9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, or3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples for partly unsaturatedheterocycloalkyl are dihydrofuryl, imidazolinyl, dihydro-oxazolyl,tetrahydro-pyridinyl, or dihydropyranyl. Particular examples ofheterocycloalkyl are saturated or partially unsaturated mono- orbicyclic 4 to 9-membered heterocycloalkyl comprising one or two ringnitrogen atoms, the remaining ring atoms being carbon. Particularexamples for monocyclic saturated heterocycloalkyl are piperidinyl andpiperazinyl. Particular example for monocyclic partially unsaturatedheterocycloalkyl is 1,2,3,6-tetrahydropyridin-4-yl. Particular examplesfor bicyclic saturated heterocycloalkyl arehexahydropyrrolo[1,2-a]pyrazin-2-yl, hexahydropyrrolo[3,4-c]pyrrol-2-yl,and 2,6-diazaspiro[3.3]heptan-2-yl. Most particular examples forheterocycloalkyl is piperazinyl.

The term “located opposite of the site of attachment” denotes theposition of an atom in a cyclic ring system. If the point of attachmentof a monocyclic ring to the rest of the molecular backbone is termedposition 1, then “located opposite of the site of attachment” denotesposition 3 for a monocylic 4-membered ring, positions 3 or 4 for amonocyclic 5-membered ring, position 4 for a monocylic 6-membered ring,and positions 4 or 5 for a monocyclic 7-membered ring. For bicyclic ringsystems, “located opposite of the site of attachment” denotes a ringatom of the second fused ring (including bridgehead atoms).

The term “aromatic” denotes the conventional idea of aromaticity asdefined in the literature, in particular in IUPAC—Compendium of ChemicalTerminology, 2nd, A. D. McNaught & A. Wilkinson (Eds). BlackwellScientific Publications, Oxford (1997).

The term “heteroaryl” denotes a monovalent aromatic heterocyclic mono-or bicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4heteroatoms selected from N, O and S, the remaining ring atoms beingcarbon. Examples of heteroaryl moieties include pyrrolyl, furanyl,thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl,pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl,isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl,benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl,benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl,purinyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl.Particular examples for heteroaryl are bicyclic 9-membered heteroarylcomprising 2 or 3 heteroatoms selected from N or O. More particularexamples for heteroaryl are imidazo[1,2-a]pyrazin-2-yl,imidazo[1,2-a]pyridin-6-yl, and benzo[d]oxazol-6-yl. Most particularheteroaryl is imidazo[1,2-a]pyridin-6-yl.

The term “alkylene” denotes a linear saturated divalent hydrocarbongroup of 2 to 7 carbon atoms or a divalent branched saturated divalenthydrocarbon group of 3 to 7 carbon atoms. Examples of alkylene groupsinclude methylene, ethylene, propylene, 2-methylpropylene, butylene,2-ethylbutylene, pentylene, hexylene. Particular examples of alkyleneare methylene and ethylene.

The term “protecting group” denotes the group which selectively blocks areactive site in a multifunctional compound such that a chemicalreaction can be carried out selectively at another unprotected reactivesite in the meaning conventionally associated with it in syntheticchemistry. Protecting groups can be removed at the appropriate point.Exemplary protecting groups are amino-protecting groups,carboxy-protecting groups or hydroxy-protecting groups.

The term “amino-protecting group” denotes groups intended to protect anamino group and includes benzyl, benzyloxycarbonyl (carbobenzyloxy,CBZ), Fmoc (9-Fluorenylmethyloxycarbonyl), p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), andtrifluoroacetyl. Particular amino-protecting group istert-butoxycarbonyl (BOC). Further examples of these groups are found inT. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis”, 2nd ed., John Wiley & Sons, Inc., New York, N.Y., 1991,chapter 7; E. Haslam, “Protective Groups in Organic Chemistry”, J. G. W.McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, and T. W.Greene, “Protective Groups in Organic Synthesis”, John Wiley and Sons,New York, N.Y., 1981. The term “protected amino group” refers to anamino group substituted by an amino-protecting groups.

The term “deprotection” or “deprotecting” denotes the process by which aprotective group is removed after the selective reaction is completed.Deprotecting reagents include acids, bases or hydrogen, in particularpotassium or sodium carbonates, lithium hydroxide in alcoholicsolutions, zinc in methanol, acetic acid, trifluoroacetic acid,palladium catalysts, or boron tribromide. Most particular deprotectingreagent is hydrochloric acid.

The term “active pharmaceutical ingredient” (or “API”) denotes thecompound or molecule in a pharmaceutical composition that has aparticular biological activity.

The term “pharmaceutical composition” refers to a preparation which isin such form as to permit the biological activity of an activeingredient contained therein to be effective, and which contains noadditional components which are unacceptably toxic to a subject to whichthe composition would be administered.

The term “pharmaceutically acceptable” denotes an attribute of amaterial which is useful in preparing a pharmaceutical composition thatis generally safe, non-toxic, and neither biologically nor otherwiseundesirable and is acceptable for veterinary as well as humanpharmaceutical use.

The term “pharmaceutically acceptable excipient” denotes any ingredienthaving no therapeutic activity and being non-toxic such asdisintegrators, binders, fillers, solvents, buffers, tonicity agents,stabilizers, antioxidants, surfactants or lubricants used in formulatingpharmaceutical products.

A “pharmaceutically acceptable carrier” refers to an ingredient in apharmaceutical composition, other than an active ingredient, which isnontoxic to a subject. A pharmaceutically acceptable carrier includes,but is not limited to, a buffer, excipient, stabilizer, or preservative.

An “individual” or “subject” is a mammal. Mammals include, but are notlimited to, domesticated animals (e.g., cows, sheep, cats, dogs, andhorses), primates (e.g., humans and non-human primates such as monkeys),rabbits, and rodents (e.g., mice and rats). In certain embodiments, theindividual or subject is a human. In a particular embodiment of theinvention the subject is a human with spinal muscular atrophy (SMA). Inanother specific embodiment, the subject is a human with SMA caused byan inactivating mutation or deletion in the SMN1 gene on bothchromosomes, resulting in a loss of SMN1 gene function.

The term “spinal muscular atrophy” (or SMA) relates to a disease causedby an inactivating mutation or deletion in the SMN1 gene on bothchromosomes, resulting in a loss of SMN1 gene function.

Symptoms of SMA include muscle weakness, poor muscle tone, weak cry,weak cough, limpness or a tendency to flop, difficulty sucking orswallowing, difficulty breathing, accumulation of secretions in thelungs or throat, clenched fists with sweaty hand, flickering/vibratingof the tongue, head often tilted to one side, even when lying down, legsthat tend to be weaker than the arms, legs frequently assuming a “froglegs” position, feeding difficulties, increased susceptibility torespiratory tract infections, bowel/bladder weakness, lower-than-normalweight, inability to sit without support, failure to walk, failure tocrawl, and hypotonia, areflexia, and multiple congenital contractures(arthrogryposis) associated with loss of anterior hom cells.

The term “treating spinal muscular atrophy (SMA)” or “treatment ofspinal muscular atrophy (SMA)” includes one or more of the followingeffects: (i) reduction or amelioration of the severity of SMA; (ii)delay of the onset of SMA; (iii) inhibition of the progression of SMA;(iv) reduction of hospitalization of a subject; (v) reduction ofhospitalization length for a subject; (vi) increase of the survival of asubject; (vii) improvement of the quality of life of a subject; (viii)reduction of the number of symptoms associated with SMA; (ix) reductionof or amelioration of the severity of one or more symptoms associatedwith SMA; (x) reduction of the duration of a symptom associated withSMA; (xi) prevention of the recurrence of a symptom associated with SMA;(xii) inhibition of the development or onset of a symptom of SMA; and/or(xiii) inhibition of the progression of a symptom associated with SMA.

More particular, “treating SMA” denotes one or more of the followingbeneficial effects: (i) a reduction in the loss of muscle strength; (ii)an increase in muscle strength; (iii) a reduction in muscle atrophy;(iv) a reduction in the loss of motor function; (v) an increase in motorneurons; (vii) a reduction in the loss of motor neurons; (viii)protection of SMN deficient motor neurons from degeneration; (ix) anincrease in motor function; (x) an increase in pulmonary function;and/or (xi) a reduction in the loss of pulmonary function.

In detail, “treating SMA” results in the functional ability or helpsretain the functional ability for a human infant or a human toddler tosit up unaided or for a human infant, a human toddler, a human child ora human adult to stand up unaided, to walk unaided, to run unaided, tobreathe unaided, to tum during sleep unaided, or to swallow unaided.

An “effective amount” of an agent, e.g., a pharmaceutical composition,refers to an amount effective, at dosages and for periods of timenecessary, to achieve the desired therapeutic or prophylactic result.

The term “preventing” or “prevention” of a disease state denotes causingthe clinical symptoms of the disease state not to develop in a subjectthat can be exposed to or predisposed to the disease state, but does notyet experience or display symptoms of the disease state.

The term “EC_(1.5×) concentration for production of full length SMN2minigene mRNA” (or “EC_(1.5×) minigene”) is defined as thatconcentration of test compound that is effective in increasing theamount of full length SMN2 minigene mRNA to a level 1.5-fold greaterrelative to that in vehicle-treated cells.

The term “EC_(1.5×) concentration for SMN protein expression” (or“EC_(1.5×) SMN protein”) is defined as that concentration of testcompound that is effective in producing 1.5 times the amount of SMNprotein in an SMA patient fibroblast cell compared to the amountproduced from the vehicle control.

In detail, the present invention relates to compounds of formula (I)

wherein

-   X is N or CR³;-   Y is N or CR⁴; with the proviso that not both X and Y are N;-   A is a bicyclic 9-membered heteroaryl comprising two or three    heteroatoms independently selected from N or O, wherein A can be    optionally substituted with one, two or three R⁵;-   B is a saturated or partially unsaturated mono- or bicyclic 4 to    9-membered heterocycloalkyl comprising one or two ring nitrogen    atoms, the remaining ring atoms being carbon, wherein B can be    optionally substituted with one, two or three R⁶;-   R¹ is hydrogen, halo, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₁₋₇-alkoxy or    C₁₋₇-haloalkoxy;-   R² is hydrogen, halo, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₁₋₇-alkoxy or    C₁₋₇-haloalkoxy;-   R³ is hydrogen, halo, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₁₋₇-alkoxy or    C₁₋₇-haloalkoxy;-   R⁴ is hydrogen, halo, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₁₋₇-alkoxy or    C₁₋₇-haloalkoxy;-   each R⁵ is independently selected from halo, cyano, C₁₋₇-alkyl,    C₁₋₇-haloalkyl or C₃₋₇-cycloalkyl;-   each R⁶ is independently selected from C₁₋₇-alkyl, or two R⁶    together form a C₂₋₇-alkylene;-   and pharmaceutically acceptable salts thereof.

Particular embodiments of the present invention are compounds of formula(I) and pharmaceutically acceptable salts thereof.

Further, it is to be understood that every embodiment relating to aspecific A, B, X, Y, R¹, R², R³, R⁴, R⁵ or R⁶ as disclosed herein may becombined with any other embodiment relating to another A, B, X, Y, R¹,R², R³, R⁴, R⁵ or R⁶ as disclosed herein.

A particular embodiment of the present invention relates to compounds offormula (I), wherein A is selected from the group ofimidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-a]pyridinyl, andbenzo[d]oxazolyl, which can be optionally substituted with one, two orthree R⁵.

A particular embodiment of the present invention relates to compounds offormula (I), wherein A is selected from the group ofimidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-a]pyridin-6-yl, andbenzo[d]oxazol-6-yl, which can be optionally substituted with one, twoor three R⁵.

A particular embodiment of the present invention relates to compounds offormula (I), wherein A is selected from the group ofimidazo[1,2-a]pyrazin-2-yl substituted with two C₁₋₇-alkyl,imidazo[1,2-a]pyridin-6-yl substituted with one or two C₁₋₇-alkyl,imidazo[1,2-a]pyridin-6-yl substituted with one C₁₋₇-alkyl and one halo,imidazo[1,2-a]pyridin-6-yl substituted with one C₁₋₇-alkyl and oneC₁₋₇-haloalkyl, benzo[d]oxazol-6-yl substituted with one C₁₋₇-alkyl, andbenzo[d]oxazol-6-yl substituted with one C₁₋₇-alkyl and one halo.

A particular embodiment of the present invention relates to compounds offormula (I), wherein A is imidazo[1,2-a]pyridinyl which can beoptionally substituted with one or two R⁵.

A particular embodiment of the present invention relates to compounds offormula (I), wherein A is imidazo[1,2-a]pyridin-6-yl substituted withone C₁₋₇-alkyl and one halo.

A particular embodiment of the present invention relates to compounds offormula (I), wherein A is selected from 2-methylbenzo[d]oxazol-6-yl,4-fluoro-2-methylbenzo[d]oxazol-6-yl,6,8-dimethylimidazo[1,2-a]pyrazin-2-yl,2-methylimidazo[1,2-a]pyridin-6-yl,2,7-dimethylimidazo[1,2-a]pyridin-6-yl,2,8-dimethylimidazo[1,2-a]pyridin-6-yl,2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl,8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl, and8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl.

A particular embodiment of the present invention relates to compounds offormula (I), wherein A is selected from8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl and8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl.

A particular embodiment of the present invention relates to compounds offormula (I), wherein each R⁵ is independently selected from halo,C₁₋₇-alkyl, or C₁₋₇-haloalkyl.

A particular embodiment of the present invention relates to compounds offormula (I), wherein each R⁵ is independently selected from methyl,fluoro, chloro, and trifluoromethyl.

A particular embodiment of the present invention relates to compounds offormula (I), wherein A is substituted by two R⁵ wherein one R⁵ is methyland the other R⁵ is fluoro or chloro.

A particular embodiment of the present invention relates to compounds offormula (I), wherein A is selected from the group of

wherein R⁵¹, R⁵² and R⁵³ are independently selected from the group ofhydrogen, halo, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl and C₃₋₇-cycloalkyl.

A particular embodiment of the present invention relates to compounds offormula (I), wherein R⁵¹, R⁵² and R⁵³ are independently selected fromthe group of hydrogen, methyl, fluoro, chloro, and trifluoromethyl.

A particular embodiment of the present invention relates to compounds offormula (I), wherein R⁵¹ is selected from hydrogen and C₁₋₇-alkyl.

A more particular embodiment of the present invention relates tocompounds of formula (I), wherein R⁵¹ is selected from hydrogen andC₁₋₂-alkyl.

A particular embodiment of the present invention relates to compounds offormula (I), wherein each R⁵² is independently selected from hydrogen,halo, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl and C₃₋₇ cycloalkyl.

A particular embodiment of the present invention relates to compounds offormula (I), wherein each R⁵² is independently selected from hydrogen,halo, cyano, C₁₋₂-alkyl, C₁₋₂-haloalkyl and cyclopropyl.

A particular embodiment of the present invention relates to compounds offormula (I), wherein each R⁵² is independently selected from hydrogenand fluoro.

A particular embodiment of the present invention relates to compounds offormula (I), wherein each R⁵³ is independently selected from hydrogen,chloro, C₁₋₇-alkyl, C₁₋₇-haloalkyl and C₃₋₇ cycloalkyl.

A particular embodiment of the present invention relates to compounds offormula (I), wherein each R⁵³ is independently selected from hydrogen,chloro, C₁₋₂-alkyl, C₁₋₂-haloalkyl and cyclopropyl.

A particular embodiment of the present invention relates to compounds offormula (I), wherein B as defined herein is further characterized inthat one ring nitrogen atoms is basic.

A particular embodiment of the present invention relates to compounds offormula (I), wherein B as defined herein is further characterized inthat its one, two or three optional substituent(s) R⁶ are attached atand/or directly adjacent to the basic ring nitrogen atoms.

A particular embodiment of the present invention relates to compounds offormula (I), wherein B is selected from 1,2,3,6-tetrahydropyridinyl,2,6-diazaspiro[3.3]heptanyl, hexahydropyrrolo[3,4-c]pyrrolyl,hexahydropyrrolo[1,2-a]pyrazinyl, piperazinyl, and piperidinyl, whereineach can be optionally substituted with one, two or three R⁶.

A particular embodiment of the present invention relates to compounds offormula (I), wherein B is selected from 1,2,3,6-tetrahydropyridin-4-yl,2,6-diazaspiro[3.3]heptan-2-yl, hexahydropyrrolo[3,4-c]pyrrol-2-yl,hexahydropyrrolo[1,2-a]pyrazin-2-yl, piperazin-1-yl, and piperidin-4-yl,wherein each can be optionally substituted with one, two or three R⁶.

A particular embodiment of the present invention relates to compounds offormula (I), wherein B is selected from 1,2,3,6-tetrahydropyridin-4-yl,and piperazin-1-yl, wherein each can be optionally substituted with one,two or three R⁶.

A particular embodiment of the present invention relates to compounds offormula (I), wherein B is piperazin-1-yl optionally substituted withone, two or three R⁶.

A particular embodiment of the present invention relates to compounds offormula (I), wherein B is selected from piperazin-1-yl,3-methyl-piperazin-1-yl, and 3,3-dimethylpiperazin-1-yl.

A particular embodiment of the present invention relates to compounds offormula (I), wherein each R⁶ is C₁₋₇ alkyl.

A particular embodiment of the present invention relates to compounds offormula (I), wherein each R⁶ is independently selected from methyl, andethyl.

A particular embodiment of the present invention relates to compounds offormula (I), wherein each R⁶ is independently selected from methyl.

A particular embodiment of the present invention relates to compounds offormula (I), wherein B is selected from the group of

wherein R⁶¹, R⁶², R⁶³ and R⁶⁴ are independently selected from hydrogenor C₁₋₇-alkyl, or wherein two of R⁶¹, R⁶² and R⁶³ together are forming aC₂₋₇-alkylene.

A particular embodiment of the present invention relates to compounds offormula (I), wherein R⁶¹, R⁶², R⁶³ and R⁶⁴ are independently selectedfrom hydrogen, methyl, and ethyl.

A particular embodiment of the present invention relates to compounds offormula (I), wherein X is CR³ and Y is CR⁴, or X is N and Y is CR⁴, or Xis CR³ and Y is N.

A particular embodiment of the present invention relates to compounds offormula (I), wherein X is CR³ and Y is CR⁴.

A particular embodiment of the present invention relates to compounds offormula (I), wherein X is N and Y is CR⁴.

A particular embodiment of the present invention relates to compounds offormula (I), wherein X is CR³ and Y is N.

A particular embodiment of the present invention relates to compounds offormula (I), wherein R¹ is hydrogen, halo, C₁₋₇-alkoxy orC₁₋₇-haloalkoxy.

A particular embodiment of the present invention relates to compounds offormula (I), wherein R¹ is hydrogen, fluoro, methoxy, ethoxy ortrifluoroethoxy.

A particular embodiment of the present invention relates to compounds offormula (I), wherein R¹ is hydrogen.

A particular embodiment of the present invention relates to compounds offormula (I), wherein R² is hydrogen, halo, or C₁₋₇-alkyl.

A particular embodiment of the present invention relates to compounds offormula (I), wherein R² is hydrogen, fluoro or methyl.

A particular embodiment of the present invention relates to compounds offormula (I), wherein R² is hydrogen.

A particular embodiment of the present invention relates to compounds offormula (I), wherein R³ is hydrogen or halo.

A particular embodiment of the present invention relates to compounds offormula (I), wherein R³ is hydrogen or fluoro.

A particular embodiment of the present invention relates to compounds offormula (I), wherein R³ is hydrogen.

A particular embodiment of the present invention relates to compounds offormula (I), wherein R⁴ is hydrogen, halo or C₁₋₇-alkoxy.

A particular embodiment of the present invention relates to compounds offormula (I), wherein R⁴ is hydrogen or halo.

A particular embodiment of the present invention relates to compounds offormula (I), wherein R⁴ is hydrogen, fluoro, methoxy, ethoxy ortrifluoroethoxy.

A particular embodiment of the present invention relates to compounds offormula (I), wherein R⁴ is hydrogen or fluoro.

Particular compounds of formula (I) of the present invention are thoseselected from the group consisting of:

-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(piperazin-1-yl)benzamide;-   rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   N-(6,8-Dimethyl-imidazo[1,2-a]pyrazin-2-yl)-4-((S)-3-methyl-piperazin-1-yl)-benzamide;-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(4-methylpiperazin-1-yl)benzamide;-   rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide;-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-methylpiperazin-1-yl)nicotinamide;-   rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-ethylpiperazin-1-yl)nicotinamide;-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(4-methylpiperazin-1-yl)picolinamide;-   rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(3-methylpiperazin-1-yl)picolinamide;-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(piperazin-1-yl)picolinamide;-   rac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;-   6-(3,3-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nicotinamide;-   N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   6-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nicotinamide;-   N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(2,6-diazaspiro[3.3]heptan-2-yl)nicotinamide;-   rac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin-1-yl)picolinamide;-   rac-2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide:-   rac-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;-   (S)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)nicotinamide;-   6-(3,5-dimethylpiperazin-1-yl)-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)nicotinamide;-   6-(3,5-dimethylpiperazin-1-yl)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)nicotinamide;-   N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-6-(4-methylpiperazin-1-yl)nicotinamide;-   (S)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinamide;-   N-(4-Fluoro-2-methyl-benzooxazol-6-yl)-6-piperazin-1-yl-nicotinamide;-   rac-N-(4-Fluoro-2-methyl-benzooxazol-6-yl)-6-(3-methyl-piperazin-1-yl)-nicotinamide;-   N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)benzamide;-   rac-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   4-(3,5-dimethylpiperazin-1-yl)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)benzamide;-   (S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)benzamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(4-methylpiperazin-1-yl)nicotinamide;-   (S)-2-Fluoro-N-(4-fluoro-2-methyl-benzooxazol-6-yl)-4-(S)-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl-benzamide;-   (R)-2-fluoro-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzamide;-   (S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)benzamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzamide;-   rac-N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide;-   rac-2-fluoro-N-(2-methylbenzo[d]oxazol-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   rac-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;-   rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin-1-yl)picolinamide;-   2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzamide;-   rac-2,3-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   rac-2,5-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   rac-5-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;-   rac-3-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin-1-yl)picolinamide;-   rac-2,6-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   (S)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   (R)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   rac-N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide;-   rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-6-(3-methylpiperazin-1-yl)nicotinamide;-   rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide;-   rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;-   rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-fluoro-5-(3-methylpiperazin-1-yl)picolinamide;-   rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2,6-difluoro-4-(3-methylpiperazin-1-yl)benzamide;-   2-fluoro-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)benzamide;-   2-fluoro-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzamide;-   2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide;-   2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)nicotinamide;-   N-(2-methylimidazo[1,2-a]pyridin-6-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)picolinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(piperazin-1-yl)nicotinamide;-   2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-methyl-4-(piperazin-1-yl)benzamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-methyl-6-(piperazin-1-yl)nicotinamide;-   4-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(piperazin-1-yl)nicotinamide;-   4-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)-4-(2,2,2-trifluoroethoxy)nicotinamide;-   2-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)-2-(2,2,2-trifluoroethoxy)nicotinamide;-   rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(3-methylpiperazin-1-yl)nicotinamide;-   6-(3,3-dimethylpiperazin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxynicotinamide;-   rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(3-methylpiperazin-1-yl)nicotinamide;-   N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)nicotinamide;-   N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperidin-4-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl)nicotinamide;-   2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperidin-4-yl)benzamide;-   rac-6-(3,4-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nicotinamide;-   and pharmaceutically acceptable salts thereof.

Particular compounds of formula (I) of the present invention are thoseselected from the group consisting of:

-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(piperazin-1-yl)benzamide;-   rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   N-(6,8-Dimethyl-imidazo[1,2-a]pyrazin-2-yl)-4-((S)-3-methyl-piperazin-1-yl)-benzamide;-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(4-methylpiperazin-1-yl)benzamide;-   rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide;-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-methylpiperazin-1-yl)nicotinamide;-   rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-ethylpiperazin-1-yl)nicotinamide;-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(4-methylpiperazin-1-yl)picolinamide;-   rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(3-methylpiperazin-1-yl)picolinamide;-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(piperazin-1-yl)picolinamide;-   rac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;-   6-(3,3-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nicotinamide;-   N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   6-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nicotinamide    hydrochloride;-   N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(2,6-diazaspiro[3.3]heptan-2-yl)nicotinamide    hydrochloride:-   rac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin-1-yl)picolinamide;-   rac-2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide:-   rac-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;-   (S)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)nicotinamide;-   6-(3,5-dimethylpiperazin-1-yl)-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)nicotinamide;-   6-(3,5-dimethylpiperazin-1-yl)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)nicotinamide;-   N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-6-(4-methylpiperazin-1-yl)nicotinamide;-   (S)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinamide;-   N-(4-Fluoro-2-methyl-benzooxazol-6-yl)-6-piperazin-1-yl-nicotinamide;-   rac-N-(4-Fluoro-2-methyl-benzooxazol-6-yl)-6-(3-methyl-piperazin-1-yl)-nicotinamide;-   N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)benzamide;-   rac-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   4-(3,5-dimethylpiperazin-1-yl)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)benzamide;-   (S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)benzamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(4-methylpiperazin-1-yl)nicotinamide;-   (S)-2-Fluoro-N-(4-fluoro-2-methyl-benzooxazol-6-yl)-4-(S)-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl-benzamide;-   (R)-2-fluoro-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzamide;-   (S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)benzamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzamide    hydrochloride;-   rac-N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide    dihydrochloride;-   rac-2-fluoro-N-(2-methylbenzo[d]oxazol-6-yl)-4-(3-methylpiperazin-1-yl)benzamide    dihydrochloride;-   rac-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide    dihydrochloride;-   2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzamide    dihydrochloride;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide    dihydrochloride;-   rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide    dihydrochloride;-   rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin-1-yl)picolinamide    dihydrochloride;-   2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzamide    hydrochloride;-   rac-2,3-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide    hydrochloride;-   rac-2,5-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide    hydrochloride;-   rac-5-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide    hydrochloride;-   rac-3-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin-1-yl)picolinamide    hydrochloride;-   rac-2,6-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide    hydrochloride;-   (S)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide    hydrochloride;-   (R)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide    hydrochloride;-   rac-N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide    dihydrochloride;-   rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-6-(3-methylpiperazin-1-yl)nicotinamide    hydrochloride;-   rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide    dihydrochloride;-   rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide    dihydrochloride;-   rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-fluoro-5-(3-methylpiperazin-1-yl)picolinamide    dihydrochloride;-   rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2,6-difluoro-4-(3-methylpiperazin-1-yl)benzamide    trihydrochloride;-   2-fluoro-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)benzamide;-   2-fluoro-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzamide;-   2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide    hydrochloride;-   2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide    hydrochloride;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)nicotinamide    dihydrochloride;-   N-(2-methylimidazo[1,2-a]pyridin-6-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)picolinamide    dihydrochloride;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(piperazin-1-yl)nicotinamide;-   2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-methyl-4-(piperazin-1-yl)benzamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-methyl-6-(piperazin-1-yl)nicotinamide;-   4-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(piperazin-1-yl)nicotinamide;-   4-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)-4-(2,2,2-trifluoroethoxy)nicotinamide;-   2-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)-2-(2,2,2-trifluoroethoxy)nicotinamide;-   rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(3-methylpiperazin-1-yl)nicotinamide;-   6-(3,3-dimethylpiperazin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxynicotinamide;-   rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(3-methylpiperazin-1-yl)nicotinamide;-   N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)nicotinamide    hydrochloride;-   N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperidin-4-yl)nicotinamide    dihydrochloride;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl)nicotinamide;-   2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperidin-4-yl)benzamide    hydrochloride;-   rac-6-(3,4-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nicotinamide;-   and pharmaceutically acceptable salts thereof.

Particular compounds of formula (I) of the present invention are thoseselected from the group consisting of:

-   rac-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   rac-3-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin-1-yl)picolinamide;-   rac-2,6-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   (S)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   (R)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide;-   rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-fluoro-5-(3-methylpiperazin-1-yl)picolinamide;-   2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)nicotinamide;-   4-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   4-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   2-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(3-methylpiperazin-1-yl)nicotinamide;-   rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(3-methylpiperazin-1-yl)nicotinamide;-   and pharmaceutically acceptable salts thereof.

A particular embodiment of the present invention relates to compounds offormula (I′)

wherein A, B, R¹, R², R³ and R⁴ are as described herein.

Particular compounds of formula (I′) of the present invention are thoseselected from the group consisting of:

-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(piperazin-1-yl)benzamide;-   rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   N-(6,8-Dimethyl-imidazo[1,2-a]pyrazin-2-yl)-4-((S)-3-methyl-piperazin-1-yl)-benzamide;-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(4-methylpiperazin-1-yl)benzamide;-   rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide;-   rac-2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)benzamide;-   rac-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   4-(3,5-dimethylpiperazin-1-yl)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)benzamide;-   (S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)benzamide;-   (S)-2-Fluoro-N-(4-fluoro-2-methyl-benzooxazol-6-yl)-4-(S)-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl-benzamide;-   (R)-2-fluoro-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzamide;-   (S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)benzamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzamide;-   rac-N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide;-   rac-2-fluoro-N-(2-methylbenzo[d]oxazol-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   rac-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzamide;-   2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzamide;-   rac-2,3-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   rac-2,5-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   rac-2,6-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   (S)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   (R)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   rac-N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide;-   rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide;-   rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2,6-difluoro-4-(3-methylpiperazin-1-yl)benzamide;-   2-fluoro-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)benzamide;-   2-fluoro-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzamide;-   2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide;-   2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-methyl-4-(piperazin-1-yl)benzamide;-   2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperidin-4-yl)benzamide;-   and pharmaceutically acceptable salts thereof.

A particular embodiment of the present invention relates to compounds offormula (I″)

wherein A, B, R¹, R² and R⁴ are as described herein.

Particular compounds of formula (I″) of the present invention are thoseselected from the group consisting of:

-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-methylpiperazin-1-yl)nicotinamide;-   rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-ethylpiperazin-1-yl)nicotinamide;-   rac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;-   6-(3,3-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nicotinamide;-   N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   6-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nicotinamide;-   N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(2,6-diazaspiro[3.3]heptan-2-yl)nicotinamide;-   N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   rac-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;-   (S)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)nicotinamide;-   6-(3,5-dimethylpiperazin-1-yl)-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)nicotinamide;-   6-(3,5-dimethylpiperazin-1-yl)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)nicotinamide;-   N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-6-(4-methylpiperazin-1-yl)nicotinamide;-   (S)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinamide;-   N-(4-Fluoro-2-methyl-benzooxazol-6-yl)-6-piperazin-1-yl-nicotinamide;-   rac-N-(4-Fluoro-2-methyl-benzooxazol-6-yl)-6-(3-methyl-piperazin-1-yl)-nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(4-methylpiperazin-1-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;-   rac-5-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;-   rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-6-(3-methylpiperazin-1-yl)nicotinamide;-   rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(piperazin-1-yl)nicotinamide;-   2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-methyl-6-(piperazin-1-yl)nicotinamide;-   4-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(piperazin-1-yl)nicotinamide;-   4-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)-4-(2,2,2-trifluoroethoxy)nicotinamide;-   2-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)-2-(2,2,2-trifluoroethoxy)nicotinamide;-   rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(3-methylpiperazin-1-yl)nicotinamide;-   6-(3,3-dimethylpiperazin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxynicotinamide;-   rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(3-methylpiperazin-1-yl)nicotinamide;-   N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)nicotinamide;-   N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperidin-4-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl)nicotinamide;-   rac-6-(3,4-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nicotinamide;-   and pharmaceutically acceptable salts thereof.

A particular embodiment of the present invention relates to compounds offormula (I″′)

wherein A, B, R¹, R² and R³ are as described herein.

Particular compounds of formula (I″′) of the present invention are thoseselected from the group consisting of:

-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(4-methylpiperazin-1-yl)picolinamide;-   rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(3-methylpiperazin-1-yl)picolinamide;-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(piperazin-1-yl)picolinamide;-   rac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin-1-yl)picolinamide;-   rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin-1-yl)picolinamide;-   rac-3-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin-1-yl)picolinamide;-   rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-fluoro-5-(3-methylpiperazin-1-yl)picolinamide;-   N-(2-methylimidazo[1,2-a]pyridin-6-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)picolinamide;-   and pharmaceutically acceptable salts thereof.

A particular embodiment of the present invention relates to compounds offormula (I^(a))

wherein B, X, Y, R¹, R², R⁵¹ and R⁵² are as described herein.

Particular compounds of formula (I^(a)) of the present invention arethose selected from the group consisting of:

-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(piperazin-1-yl)benzamide;-   rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   N-(6,8-Dimethyl-imidazo[1,2-a]pyrazin-2-yl)-4-((S)-3-methyl-piperazin-1-yl)-benzamide;-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(4-methylpiperazin-1-yl)benzamide;-   rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide;-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-methylpiperazin-1-yl)nicotinamide;-   rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-ethylpiperazin-1-yl)nicotinamide;-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(4-methylpiperazin-1-yl)picolinamide;-   rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(3-methylpiperazin-1-yl)picolinamide;-   N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(piperazin-1-yl)picolinamide;-   and pharmaceutically acceptable salts thereof.

A particular embodiment of the present invention relates to compounds offormula (I^(b))

wherein B, X, Y, R¹, R², R⁵¹, R⁵² and R⁵³ are as described herein.

Particular compounds of formula (I^(b)) of the present invention arethose selected from the group consisting of:

-   rac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;-   6-(3,3-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nicotinamide;-   N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   6-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nicotinamide;-   N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(2,6-diazaspiro[3.3]heptan-2-yl)nicotinamide;-   rac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin-1-yl)picolinamide;-   rac-2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   rac-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;-   (S)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)nicotinamide;-   6-(3,5-dimethylpiperazin-1-yl)-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)nicotinamide;-   (S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)benzamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(4-methylpiperazin-1-yl)nicotinamide;-   (S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)benzamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzamide;-   rac-N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide;-   rac-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;-   rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin-1-yl)picolinamide;-   2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzamide;-   rac-2,3-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   rac-2,5-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   rac-5-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;-   rac-3-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin-1-yl)picolinamide;-   rac-2,6-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   (S)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   (R)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   rac-N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide;-   rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-6-(3-methylpiperazin-1-yl)nicotinamide;-   rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide;-   rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;-   rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-fluoro-5-(3-methylpiperazin-1-yl)picolinamide;-   rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2,6-difluoro-4-(3-methylpiperazin-1-yl)benzamide;-   2-fluoro-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzamide;-   2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide;-   2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)nicotinamide;-   N-(2-methylimidazo[1,2-a]pyridin-6-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)picolinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(piperazin-1-yl)nicotinamide;-   2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-methyl-4-(piperazin-1-yl)benzamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-methyl-6-(piperazin-1-yl)nicotinamide;-   4-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(piperazin-1-yl)nicotinamide;-   4-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)-4-(2,2,2-trifluoroethoxy)nicotinamide;-   2-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)-2-(2,2,2-trifluoroethoxy)nicotinamide;-   rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(3-methylpiperazin-1-yl)nicotinamide;-   6-(3,3-dimethylpiperazin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxynicotinamide;-   rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(3-methylpiperazin-1-yl)nicotinamide;-   N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)nicotinamide;-   N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperidin-4-yl)nicotinamide;-   N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl)nicotinamide;-   2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperidin-4-yl)benzamide;-   rac-6-(3,4-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nicotinamide;-   and pharmaceutically acceptable salts thereof.

A particular embodiment of the present invention relates to compounds offormula (I^(c))

wherein B, X, Y, R¹, R², R⁵¹, and R⁵² are as described herein.

Particular compounds of formula (I^(c)) of the present invention arethose selected from the group consisting of:

-   6-(3,5-dimethylpiperazin-1-yl)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)nicotinamide;-   N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-6-(4-methylpiperazin-1-yl)nicotinamide;-   (S)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinamide;-   N-(4-Fluoro-2-methyl-benzooxazol-6-yl)-6-piperazin-1-yl-nicotinamide;-   rac-N-(4-Fluoro-2-methyl-benzooxazol-6-yl)-6-(3-methyl-piperazin-1-yl)-nicotinamide;-   N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)benzamide;-   rac-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   4-(3,5-dimethylpiperazin-1-yl)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)benzamide;-   (S)-2-Fluoro-N-(4-fluoro-2-methyl-benzooxazol-6-yl)-4-(S)-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl-benzamide;-   (R)-2-fluoro-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzamide;-   rac-2-fluoro-N-(2-methylbenzo[d]oxazol-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;-   2-fluoro-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)benzamide;-   and pharmaceutically acceptable salts thereof.

Manufacturing Processes

Compounds of formula (I) and pharmaceutically acceptable salts thereofas defined above be prepared following standard methods known in theart.

In a particular embodiment, the invention further relates to a processfor the manufacture of compounds of formula (I) and pharmaceuticallyacceptable salts thereof as defined above, comprising:

-   a) the Buchwald-Hartwig amination reaction of a compound of formula    (II)

-   -   with a compound of formula B—H, in the presence of a catalyst        (e.g. tris(dibenzylidene-acetone)dipalladium(0) (Pd₂(dba)₃)) and        a ligand (e.g. 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl        (BINAP)) and a base (e.g. cesium carbonate) and a solvent (e.g.        toluene), wherein the hydrogen H of the compound of formula B—H        is bound to a ring nitrogen atom of B, V is chloro or bromo, and        A, B, X, Y, R¹, and R² are as defined above; or

-   b) a nucleophilic aromatic substitution reaction between a compound    of formula (II) with a compound of formula B—H by heating (e.g.    T=120° C.-200° C.) in a solvent (e.g. dimethyl sulfoxide (DMSO),    N-methylpyrrolidone (NMP), or dimethylformamide (DMF)), wherein the    hydrogen H of the compound of formula B—H is bound to a ring    nitrogen atom of B, V is fluoro if X is CR³ or V is chloro if X is    N, and A, B, X, Y, R¹, R² and R³ are as defined above; or

-   c) the Suzuki coupling reaction of a compound of formula (II) with a    compound of formula PG-B-pinB in the presence of a base (e.g. K₂CO₃)    and a catalyst (e.g. PdCl₂), followed by removal of PG, wherein pinB    is pinacolboranyl (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)    which is bound to a ring carbon atom of B, PG is an amino-protecting    group such as tert-butoxycarbonyl (BOC), V is fluoro or chloro, and    wherein A, B, X, Y, R¹, and R² are as defined above; or

-   d) the amidation reaction of a compound of formula (III)

-   -   with a compound of formula A-NH₂ in the presence of a tertiary        amine (e.g. N,N-diisopropylethylamine (DIPEA) or triethylamine        (TEA)) and a coupling reagent (e.g.        2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate methanaminium (HATU) or        O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        tetrafluoroborate (TBTU)), optionally followed by the removal of        PG, wherein PG is an optional amino-protecting group such as        tert-butoxycarbonyl (PG), and wherein A, B, X, Y, R¹, and R² are        as defined above.

Particularly, compounds of formula (I) and pharmaceutically acceptablesalts thereof can be prepared in accordance to the methods described inthe examples herein.

Pharmaceutical Compositions

Another embodiment provides pharmaceutical compositions or medicamentscomprising the compounds of the invention and a therapeutically inertcarrier, diluent or pharmaceutically acceptable excipient, as well asmethods of using the compounds of the invention to prepare suchcompositions and medicaments.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularmammal being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners.

The compounds of the invention may be administered by any suitablemeans, including oral, topical (including buccal and sublingual),rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal,intrapulmonary, intradermal, intrathecal and epidural and intranasal,and, if desired for local treatment, intralesional administration.Parenteral infusions include intramuscular, intravenous, intraarterial,intraperitoneal, or subcutaneous administration.

The compounds of the present invention may be administered in anyconvenient administrative form, e.g., tablets, powders, capsules,solutions, dispersions, suspensions, syrups, sprays, suppositories,gels, emulsions, patches, etc. Such compositions may comprise componentsconventional in pharmaceutical preparations, e.g., diluents, carriers,pH modifiers, preservatives, solubilizers, stabilizers, wetting agents,emulsifiers, sweeteners, colorants, flavorants, salts for varying theosmotic pressure, buffers, masking agents, antioxidants, and furtheractive agents. They can also comprise still other therapeuticallyvaluable substances.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier or excipient. Suitable carriers and excipientsare well known to those skilled in the art and are described in detailin, e.g., Ansel H. C. et al., Ansel's Pharmaceutical Dosage Forms andDrug Delivery Systems (2004) Lippincott, Williams & Wilkins,Philadelphia; Gennaro A. R. et al., Remington: The Science and Practiceof Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; andRowe R. C, Handbook of Pharmaceutical Excipients (2005) PharmaceuticalPress, Chicago. The formulations may also include one or more buffers,stabilizing agents, surfactants, wetting agents, lubricating agents,emulsifiers, suspending agents, preservatives, antioxidants, opaquingagents, glidants, processing aids, colorants, sweeteners, perfumingagents, flavoring agents, diluents and other known additives to providean elegant presentation of the drug (i.e., a compound of the presentinvention or pharmaceutical composition thereof) or aid in themanufacturing of the pharmaceutical product (i.e., medicament).

The dosage at which compounds of the invention can be administered canvary within wide limits and will, of course, be fitted to the individualrequirements in each particular case. In general, in the case of oraladministration a daily dosage of about 0.01 to 1000 mg per person of acompound of general formula (I) should be appropriate, although theabove upper limit can also be exceeded when necessary.

An example of a suitable oral dosage form is a tablet comprising about100 mg to 500 mg of the compound of the invention compounded with about30 to 90 mg anhydrous lactose, about to 40 mg sodium croscarmellose,about 5 to 30 mg polyvinylpyrrolidone (PVP) K30, and about 1 to 10 mgmagnesium stearate. The powdered ingredients are first mixed togetherand then mixed with a solution of the PVP. The resulting composition canbe dried, granulated, mixed with the magnesium stearate and compressedto tablet form using conventional equipment.

An example of an aerosol formulation can be prepared by dissolving thecompound, for example 10 to 100 mg, of the invention in a suitablebuffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. asalt such as sodium chloride, if desired. The solution may be filtered,e.g., using a 0.2 μm filter, to remove impurities and contaminants.

Uses

As described above, the compounds of formula (I) and theirpharmaceutically acceptable salts possess valuable pharmacologicalproperties and have been found to be enhancing inclusion of exon 7 ofSMN1 and/or SMN2 into mRNA transcribed from the SMN1 and/or SMN2 gene,thereby increasing expression of SMN protein in a human subject in needthereof.

The compounds of the present invention can be used, either alone or incombination with other drugs, for the treatment or prevention ofdiseases caused by an inactivating mutation or deletion in the SMN1 geneand/or associated with loss or defect of SMN1 gene function. Thesediseases include, but are not limited to spinal muscular atrophy (SMA).

A particular embodiment of the present invention relates topharmaceutical compositions comprising compounds of formula (I) asdefined above or their pharmaceutically acceptable salts as definedabove and one or more pharmaceutically acceptable excipients.

A particular embodiment of the present invention relates topharmaceutical compositions comprising compounds of formula (I) or theirpharmaceutically acceptable salts as defined above and one or morepharmaceutically acceptable excipients for the treatment or preventionof diseases caused by an inactivating mutation or deletion in the SMN1gene and/or associated with loss or defect of SMN1 gene function,particularly for the treatment or prevention of spinal muscular atrophy(SMA).

A particular embodiment of the present invention relates to compounds offormula (I) or their pharmaceutically acceptable salts as defined abovefor use as therapeutically active substances, especially for use astherapeutically active substances for the treatment or prevention ofdiseases caused by an inactivating mutation or deletion in the SMN1 geneand/or associated with loss or defect of SMN1 gene function,particularly for the treatment or prevention of spinal muscular atrophy(SMA).

A particular embodiment of the present invention relates to compounds offormula (I) or their pharmaceutically acceptable salts as defined abovefor the use in the treatment or prevention of diseases caused by aninactivating mutation or deletion in the SMN1 gene and/or associatedwith loss or defect of SMN1 gene function, particularly for use in thetreatment or prevention of spinal muscular atrophy (SMA).

A particular embodiment of the present invention relates to a method forthe treatment or prevention of diseases caused by an inactivatingmutation or deletion in the SMN1 gene and/or associated with loss ordefect of SMN1 gene function, particularly for the treatment orprevention of spinal muscular atrophy (SMA), which method comprisesadministering compounds of formula (I) or their pharmaceuticallyacceptable salts as defined above to a subject.

A particular embodiment of the present invention relates to the use ofcompounds of formula (I) or their pharmaceutically acceptable salts asdefined above for the treatment or prevention of diseases caused by aninactivating mutation or deletion in the SMN1 gene and/or associatedwith loss or defect of SMN1 gene function, particularly for thetreatment or prevention of spinal muscular atrophy (SMA).

A particular embodiment of the present invention relates to the use ofcompounds of formula (I) or their pharmaceutically acceptable salts asdefined above for the preparation of medicaments for the treatment orprevention of diseases caused by an inactivating mutation or deletion inthe SMN1 gene and/or associated with loss or defect of SMN1 genefunction, particularly for the treatment or prevention of spinalmuscular atrophy (SMA). Such medicaments comprise compounds of formula(I) or their pharmaceutically acceptable salts as defined above.

EXAMPLES

The invention will be more fully understood by reference to thefollowing examples. They should however not be construed as limiting thescope of the invention.

Preparation of Intermediates Example A.1 Preparation ofN-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-fluorobenzamide

To a mixture of 6,8-dimethylimidazo[1,2-a]pyrazin-2-aminetrihydrochloride (Example B.1) (134 mg, 494 μmol) andN-Ethyldiisopropylamine (320 mg, 420 μl, 2.47 mmol) in dioxane (2.0 ml)was added dropwise a solution of 4-fluorobenzoyl chloride (80 mg, 60.3μl, 494 μmol) in dioxane (0.5 ml) at room temperature. The mixture wasstirred for 1 hour. The solvent was removed in vacuo. The solid wastaken in water and the suspension was stirred for 15 minutes. The solidwas filtered and dried to provide 125 mg (89%) of the title compound asan off-white solid. MS (m/e): 285.4 (M+H+)

In analogy to Example A. 1, Examples A.2 to A.7 of the following tablewere prepared from the acylchloride and amine derivatives:

Example No. Structure Systematic Name Starting materials A.2

N-(6,8- dimethylimidazo[1,2- a]pyrazin-2-yl)-2,4- difluorobenzamide6,8-dimethylimidazo[1,2- a]pyrazin-2-amine trihydrochloride (ExampleB.1)and 2,4- difluorobenzoyl chloride (commercial) A.3

6-chloro-N-(6,8- dimethylimidazo[1,2- a]pyrazin-2- yl)nicotinamide6,8-dimethylimidazo[1,2- a]pyrazin-2-amine trihydrochloride (ExampleB.1)and 6- chloronicotinoyl chloride (commercial) A.4

N-(6,8- dimethylimidazo[1,2- a]pyrazin-2-yl)-5- fluoropicolinamide6,8-dimethylimidazo[1,2- a]pyrazin-2-amine trihydrochloride (ExampleB.1) and 5-Fluoro- pyridine-2-carbonyl chloride (717871-83-5) A.5

6-chloro-N-(2- methylimidazo[1,2- a]pyridin-6- yl)nicotinamide2-methylimidazo[1,2- a]pyridin-6-amine hydrobromide (commercial) and 6-chloronicotinoyl chloride (commercial) A.6

5-fluoro-N-(2- methylimidazo[1,2- a]pyridin-6- yl)picolinamide2-methylimidazo[1,2- a]pyridin-6-amine hydrobromide (commercial) and 5-Fluoro-pyridine-2- carbonyl chloride (717871-83-5) A.7

2,4-difluoro-N-(2- methylimidazo[1,2- a]pyridin-6- yl)benzamide2-methylimidazo[1,2- a]pyridin-6-amine hydrobromide (commercial) and2,4- difluorobenzoyl chloride (commercial)

Example A.8 Preparation of6-Chloro-N-(2-methyl-8-trifluoromethyl-imidazo[1,2-a]pyridin-6-yl)-nicotinamide

To a solution of 6-chloronicotinic acid (332 mg, 2.11 mmol) in DMF (4ml) under argon at room temperature, were added HATU(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate) (1.2 g, 3.16 mmol) and N,N-diisopropylethylamine(1.4 ml, 8.42 mmol). After 5 minutes stirring,2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-amine hydrochloride(Example B.2) (530 mg, 2.11 mmol) was added. The mixture was stirred atroom temperature for two days. The solvent was removed in vacuo. Theresidue was taken in aqueous bicarbonate. The aqueous layer wasextracted 3 times with ethyl acetate. The combined extracts were driedover sodium sulfate, filtered and concentrated in vacuo. The crudemixture was purified with flash column chromatography on silica elutingwith a gradient formed from dichloromethane and methanol (0 to 5%) toprovide the title compound.

In analogy to Example A.8, Examples A.9 to A.10 of the following tablewere prepared from the acid and amine derivatives:

Example No. Structure Systematic Name Starting materials A.9 

6-chloro-N-(4-fluoro-2- methylbenzo[d] oxazol-6- yl)nicotinamide4-fluoro-2- methylbenzo[d]oxazol- 6-amine hydrochloride (Example B.3)and 6- chloronicotinic acid (commercial) A.10

4-fluoro-N-(4-fluoro-2- methylbenzo[d] oxazol-6- yl)benzamide4-fluoro-2- methylbenzo[d] oxazol- 6-amine hydrochloride (Example B.3)and 4- fluorobenzoic acid (commercial)

Example B.1 Preparation of 6,8-dimethylimidazo[1,2-a]pyrazin-2-aminetrihydrochloride

a) Step 1 Ethyl 6,8-dimethylimidazo[1,2-a]pyrazine-2-carboxylatehydrobromide

To a solution of 3,5-dimethylpyrazin-2-amine (200 mg, 1.62 mmol) in DME(6.00 ml) was added ethyl 3-bromo-2-oxopropanoate (380 mg, 245 μl, 1.95mmol) at 0° C. The mixture was stirred for 2 hours at room temperature.The suspension was filtered and washed with dimethoxyethane. Thefiltrate was taken in ethanol (4 ml) and refluxed for 1.5 hours. Thereaction mixture was cooled to room temperature, filtered and washedwith ethanol to provide 323 mg (66.3%) of the title compound as a lightyellow solid. MS (m/e): 220.1 (M+H+)

b) Step 2 6,8-dimethylimidazo[1,2-a]pyrazine-2-carboxylic acidhydrochloride

To a solution of ethyl 6,8-dimethylimidazo[1,2-a]pyrazine-2-carboxylatehydrobromide (300 mg, 0.999 mmol) in ethanol (6 ml) and water (3 ml)under nitrogen at room temperature, was added sodium hydroxide 2M (1.05ml, 2.1 mmol). The reaction mixture was stirred at 90° C. for 2 hours.The mixture was cooled to room temperature and acidified with 1 ml HClsolution (2 M). The resulting suspension was cooled to 0° C., filtered,washed with cold diethyl ether and dried to provide 128 mg (56.3%) ofthe title compound as a light brown solid. MS (m/e): 192.1 (M+H+)

c) Step 3 tert-butyl 6,8-dimethylimidazo[1,2-a]pyrazin-2-ylcarbamate

To a suspension of 6,8-dimethylimidazo[1,2-a]pyrazine-2-carboxylic acidhydrochloride (5 g, 22.0 mmol) in tert-butanol (50.9 ml) under nitrogeneat room temperature, was added triethylamine (9.17 ml, 65.9 mmol). Afterstirring for 10 minutes, diphenylphosphoryl azide (4.85 ml, 22.0 mmol)was added. The reaction mixture was stirred at 85° C. overnight.

The solvent was removed in vacuo. The residue was taken in aqueousbicarbonate. The aqueous layer was extracted 3 times with ethyl acetate.The combined extracts were dried over sodium sulfate, filtered andconcentrated in vacuo. The crude orange oil was purified with flashcolumn chromatography on silica eluting with a gradient formed fromn-heptane and ethyl acetate (0 to 60%) to provide 3.57 g (y: 62.0%) ofthe title compound as a white foam. MS(m/e): 263.5 (M+H+)

d) Step 4 6,8-dimethylimidazo[1,2-a]pyrazin-2-amine trihydrochloride

To a yellow solution of tert-butyl6,8-dimethylimidazo[1,2-a]pyrazin-2-ylcarbamate (3.57 g, 13.6 mmol) inmethanol (35.7 ml) under nitrogene at room temperature, was addeddropwise hydrogen chloride (34.0 ml, 136 mmol, 4M in dioxane). Thereaction mixture was stirred at room temperature overnight. The mixturewas evaporated to provide 3.66 g (99%) of the title compound as a yellowsolid. MS(m/e): 163.2 (M+H+)

Example B.2 Preparation of2-Methyl-8-trifluoromethyl-imidazo[1,2-a]pyridin-6-ylamine hydrochloride

a) Step 1 6-bromo-2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine

In a 30 ml sealed reactor, 5-bromo-3-(trifluoromethyl)pyridin-2-amine(CAS:79456-34-1) (2.5 g, 10.4 mmol) was combined with1-chloropropan-2-one (1.04 ml, 12.4 mmol) in acetonitrile (25 ml) andheated at 130° C. for 2 days. The reaction mixture was cooled to roomtemperature, quenched with 100 ml of a saturated aqueous sodiumbicarbonate solution. The reaction was extracted with ethylacetate andwater. The organic layers were dried over sodium sulfate andconcentrated in vacuo. The crude residue was purified with flash columnchromatography on silica eluting with a gradient formed from n-heptaneand ethyl acetate (0 to 25%) to provide 1.2 g (y: 41.5%) of the titlecompound as a pink solid.

b) Step 2N-(diohenylmethylene)-2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-amine

In a 250 mL pear-shaped flask,6-bromo-2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine (2.79 g, 10.0mmol), rac 2,2′-bis(diphenylphosphino)-1,1′-binaphtalene (623 mg, 1.00mmol), palladium (II) acetate (224 mg, 1.00 mmol), cesium carbonate(8.14 g, 25.0 mmol) and diphenylmethanimine (2.48 g, 2.3 ml, 13.0 mmol)were combined with THF (70 ml) to give a orange suspension. The reactionmixture was heated to 70° C. and stirred for 23 h. The reaction wasextracted with ethylacetate and water. The organic layers were driedover sodium sulfate and concentrated in vacuo. The crude residuepurified with flash column chromatography on silica eluting with agradient formed from n-heptane and ethyl acetate (0 to 25%) to provide2.33 g (y: 61.0%) of the title compound as a yellow oil. MS(m/e): 380.5(M+H+).

c) Step 3 2-Methyl-8-trifluoromethyl-imidazo[1,2-a]pyridin-6-ylaminehydrochloride

To a solution ofN-(diohenylmethylene)-2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-amine(2.3 g, 6.06 mmol) in dioxane (20 ml) was added HCl 1N (7.58 ml, 7.58mmol). The mixture was stirred at room temperature for 30 minutes. Thesolvent was removes in vacuo. The residue was triturated inacetonitrile. The white solid was filtered, washed with acetonitrile anddried to provide 1.08 g (71%) of the expected compound as a white solid.MS (m/e): 216.5 (M+H+)

Example B.3 Preparation of 4-fluoro-2-methylbenzo[d]oxazol-6-aminehydrochloride

a) Step 1 6-Bromo-4-fluoro-2-methyl-benzooxazole

To a solution of 4′-bromo-2′,6′-difluoroacetanilide (4.0 g, 15.6 mmol,CAS: 658072-14-1) in N-methyl-2-pyrrolidinone (25 ml) was added cesiumcarbonate (10.3 g, 31.6 mmol) and the mixture heated to 150° C. for 1 h.The reaction was then diluted with water and extracted with ethylacetate. The organic phase was washed with brine, dried over sodiumsulfate and concentrated in vacuo. The crude residue was purified withflash column chromatography on silica eluting with a gradient formedfrom n-heptane and ethyl acetate (20% to 50%) to provide 1.5 g (42%) ofthe title compound as a light brown solid. MS (m/e): 273.1 (M+H+MeCN).

B) STEP 2 4-fluoro-2-methylbenzo[d]oxazol-6-amine hydrochloride

In analogy to the procedure described for the synthesis of example B.2(steps: 2-3), the title compound was prepared from6-Bromo-4-fluoro-2-methyl-benzooxazole. MS (m/e): 216.5 (M+H+).

Example B.4 Preparation of8-Fluoro-2-methyl-imidazo[1,2-a]pyridin-6-ylamine hydrochloride

In analogy to the procedure described for the synthesis of example B.2(steps: 1-3), the title compound was prepared from5-bromo-3-fluoro-pyridin-2-ylamine (CAS: 748812-37-5). MS (m/e): 166.2(M+H+).

Example B.5 Preparation of8-chloro-2-methylimidazo[1,2-a]pyridin-6-amine hydrochloride

In analogy to the procedure described for the synthesis of example B.2(steps: 1-3), the title compound was prepared from5-bromo-3-chloro-pyridin-2-ylamine (CAS: 38185-55-6). MS (m/e): 182.1(M+H+).

Example C.1 Preparation of(S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzoic acid

a) Step 1 (S)-methyl2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzoate

Toluene (1.5 ml) was added to a mixture of methyl4-bromo-2-fluorobenzoate (200 mg, 832 μmol) and(S)-octahydropyrrolo[1,2-a]pyrazine (130 mg, 999 μmol). The mixture wasstirred until complete dissolution. Then cesium carbonate (407 mg, 1.25mmol) was added. Then Pd₂(dba)₃ (22.9 mg, 25.0 μmol) and BINAP (46.7 mg,74.9 μmol) were added. The reaction mixture was stirred vigorously for24 hours at 110° C. The reaction mixture was cooled to room temperature.Water and ethylacetate were added. The layers were separated. Theaqueous layer was extracted twice with ethylacetate. The combinedorganic layers were washed with water, dried over sodium sulfate,filtered and evaporated. The crude orange oil was purified with flashcolumn chromatography on silica eluting with a gradient formed fromn-heptane and ethyl acetate (0 to 80%) to provide 121 mg (y: 52.2%) ofthe title compound as a yellow oil MS (m/e): 279.5 (M+H+)

b) Step 2(S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzoic acid

To a solution of (S)-methyl2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzoate (100 mg,359 μmol) in tetrahydrofuran (513 μl), methanol (256 μl) and water (256μl) was added lithium hydroxide monohydrate (45.2 mg, 1.08 mmol). Themixture was stirred at room temperature for 6 hours. The mixture wasevaporated. HCl 2N was added dropwise to pH 3-4. Dichloromethane wasadded and the aqueous layer was extracted 3 times with dichloromethaneNaOH 5N was added to the aqueous phase to reach pH 6. The solution wasevaporated. The residue was suspended in dichloromethane and methanol,filtered and evaporated to provide 82 mg (86.4%) of the title compoundas colorless oil. MS (m/e): 265.5 (M+H+)

Example C.2 Preparation of(R)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzoic acid

In analogy to the procedure described for the synthesis of example C.1(steps: 1-2), the title compound was prepared from4-bromo-2-fluorobenzoate and (R)-octahydropyrrolo[1,2-a]pyrazine.

Example C.3 Preparation ofrac-4-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)-2-fluorobenzoicacid

a) Step 1 rac-tert-butyl4-(4-(ethoxycarbonyl)-3-fluorophenyl)-2-methylpiperazine-1-carboxylate

A solution of ethyl 2,4-difluorobenzoate (200 mg, 1.07 mmol) and2-methylpiperazine (538 mg, 5.37 mmol) in DMA (2 ml) was heated to 100°C. in a microwave reactor for 15 minutes.

Ethyl acetate and water was added. The layers were separated and theaqueous layer was extracted twice with ethyl acetate. The combinedorganic layers were dried over sodium sulfate, filtered and evaporated.A solution of this crude material and triethylamine (131 mg, 180 μl,1.29 mmol) in dichloromethane (2.00 ml) was cooled to 0° C.Di-tert-butyl dicarbonate (352 mg, 1.61 mmol) in dichloromethane (0.5ml) was added dropwise. The mixture was stirred at room temperatureovernight. Water was added. The layers were separated. The aqueous layerwas extracted twice with dichloromethane. The combined organic layerswere dried over sodiumsulfate, filtered and evaporated. The crudeproduct was purified with flash column chromatography on silica gel(Eluent: Heptane/ethyl acetate 0 to 20) to provide 155 mg (34%) of thetitle compound as a light yellow oil.

b) Step 2rac-4-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)-2-fluorobenzoicacid

In analogy to the procedure described for the synthesis of example C.1(step: 2), the title compound was prepared from rac-tert-butyl4-(4-(ethoxycarbonyl)-3-fluorophenyl)-2-methylpiperazine-1-carboxylate

Example C.4 Preparation ofrac-4-(6-Carboxy-pyridin-3-yl)-2-methyl-piperazine-1 carboxylic acidtert-butyl ester

A solution of 5-fluoropicolinic acid (0.47 g, 3.33 mmol) and2-methylpiperazine N1 Boc (1.00 g, 5.00 mmol) in DMA (2.00 ml) washeated to 160° C. in a microwave reactor for 1 hour. The solvent wasevaporated under high vacuum. The residue was taken in water andacidified to pH 3. The aqueous phase was extracted 3 times with ethylacetate, dried and concentrated. The crude product was purified withflash column chromatography on silica gel (Eluent: Heptane/ethyl acetate0 to 20) to provide 1.17 g (100%) of the title compound.

Example C.5 Preparation ofrac-4-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)-2,3-difluorobenzoicacid

In analogy to the procedure described for the synthesis of example C.3(steps: 1-2), the title compound was prepared from2,3,4-trifluoro-benzoic acid ethyl ester and rac-2-methylpiperazine.

Example C.6 Preparation ofrac-4-(4-Carboxy-2,5-difluoro-phenyl)-2-methyl-piperazine-1-carboxylicacid tert-butyl ester

In analogy to the procedure described for the synthesis of example C.3(steps: 1-2), the title compound was prepared from2,4,5-Trifluoro-benzoic acid methyl ester and rac-2-methylpiperazine.

Example C.7 Preparation ofrac-6-(4-(tertbutoxycarbonyl)-3-methylpiperazin-1-yl)-5-fluoronicotinicacid

In analogy to the procedure described for the synthesis of example C.3(steps: 1-2), the title compound was prepared from6-Chloro-5-fluoro-nicotinic acid methyl ester andrac-2-methylpiperazine.

Example C.8 Preparation ofrac-5-(4-(tertbutoxycarbonyl)-3-methylpiperazin-1-yl)-3-fluoropicolinicacid

In analogy to the procedure described for the synthesis of example C.3(steps: 1-2), the title compound was prepared from3,5-Difluoro-pyridine-2-carboxylic acid methyl ester andrac-2-methylpiperazine.

Example C.9 Preparation ofrac-4-(4-(tertbutoxycarbonyl)-3-methylpiperazin-1-yl)-2,6-difluorobenzoicacid

In analogy to the procedure described for the synthesis of example C.3(steps: 1-2), the title compound was prepared from2,4,6-Trifluoro-benzoic acid methyl ester and rac-2-methylpiperazine.

Example C.10 Preparation of(S)-4-(4-(tertbutoxycarbonyl)-3-methylpiperazin-1-yl)-2-fluorobenzoicacid

In analogy to the procedure described for the synthesis of example C.1(steps: 1-2), the title compound was prepared from methyl4-bromo-2-fluorobenzoate and (S)-tert-butyl2-methylpiperazine-1-carboxylate.

Example C.11 Preparation of(R)-4-(4-(tertbutoxycarbonyl)-3-methylpiperazin-1-yl)-2-fluorobenzoicacid

In analogy to the procedure described for the synthesis of example C.1(steps: 1-2), the title compound was prepared from methyl4-bromo-2-fluorobenzoate and (R)-tert-butyl2-methylpiperazine-1-carboxylate.

Example C.12 Preparation of4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzoicacid

a) Step 1 tert-butyl4-(3-fluoro-4-(methoxycarbonyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate

To a solution of methyl 4-bromo-2-fluorobenzoate (94 mg, 395 μmol) inDioxane (2 ml) were added tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(179.3 mg, 580 μmol), tetrakis-(triphenylphosphine)palladium (22.8 mg,19.8 μmol, Eq: 0.05) and tripotassium phosphate (170.1 mg, 801 μmol).Under an inert atmosphere, the mixture was heated at 100° C. for 18 h.The reaction was filtered and the filtrate was concentrated in vacuo.The resulting brown oil was purified by flash column chromatography onsilica (Eluent: Heptane/ethyl acetate 0 to 20) to provide 121 mg (91%)of the title compound as a light yellow oil. MS (m/e): 280.4 (M+H-56)

b) Step 24-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzoicacid

In analogy to the procedure described for the synthesis of example C.1(step: 2), the title compound was prepared from tert-butyl4-(3-fluoro-4-(methoxycarbonyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate

Example C.13 Preparation of6-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)nicotinic acid

To a solution of 6-chloronicotinic acid (200 mg, 1.26 mmol) in dry DMF(2.5 ml) under nitrogen at room temperature, were added tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(466 mg, 1.51 mmol), tetrakis(triphenylphosphine) palladium (0) (147 mg,126 μmol) and potassium carbonate anhydrous (521 mg, 3.77 mmol). Thereaction mixture was degased with nitrogen for 10 minutes. The mixturewas then stirred at 125° C. in microwave for 45 min. The mixture wasdiluted with DMF. Water was added to the suspension and the mixture wascooled to 0° C. HCl 1N was slowly added, until pH 3-4. The suspensionwas filtered and the solid was washed with water and then ethyl acetateto provide 158 mg (41.3%) of the title compound as a white solid. MS(m/e): 305.5 (M+H+)

Example C.14 Preparation of5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)picolinic acid

a) Step 1 methyl5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)picolinate

To a solution of methyl 5-bromopicolinate (205 mg, 930 μmol) in DMF (2ml) under nitrogen at room temperature, was added tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(300 mg, 970 μmol), followed by sodium carbonate 2M aq. (650 μl, 1.3mmol). The reaction mixture was degased with argon for 10 minutes.Finally, dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (30.5 mg, 41.7 μmol) was added and the mixturewas then stirred at 60° C. in microwave for 10 minutes, and then 70° C.for 70 minutes. Ethyl acetate and water were added to the reactionmixture. Both layers were separated and the aqueous layer was extractedtwo times with ethyl acetate. The combined organic layers were driedover sodium sulfate, filtered and concentrated in vacuo. The crude brownoil was purified with flash column chromatography on silica (Eluent:Heptane/ethyl acetate 0 to 20) to provide 202 mg (68%) of the titlecompound as a white solid. MS (m/e): 319.5 (M+H-56)

b) Step 24-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzoicacid

In analogy to the procedure described for the synthesis of example C.1(step: 2), the title compound was prepared from methyl5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)picolinate.

Example C.15 Preparation of6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-methoxynicotinic acid

a) Step 1 tert-butyl4-(6-fluoro-5-(methoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate

To an ice-cold solution of methyl 2,6-difluoronicotinate (2.0 g, 11.6mmol, CAS 11767-02-0) and triethylamine (1.6 ml, 11.6 mmol) in DMF (10ml) was added dropwise a solution of tert-butyl piperazine-1-carboxylate(2.2 g, 11.6 mmol) in DMF (5 ml). The reaction was stirred for 0.5 h at0° C. after which time it was diluted with ethyl acetate, washed withwater, brine, dried over sodium sulfate, filtered and concentrated invacuo. The crude oil was purified with flash column chromatography onsilica (Eluent: Heptane/ethyl acetate 10 to 20%) to provide 2.7 g (68%)of the title compound as a white solid. MS (m/e): 340.2 (M+H).

b) Step 2 tert-butyl4-(6-methoxy-5-(methoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(6-fluoro-5-(methoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate(0.40 g, 1.2 mmol) in methanol (5 ml) was added potassium tert-butoxide(0.13 g, 1.2 mmol) and the mixture heated to reflux. After 4 h thereaction was diluted with dichloromethane, washed with brine, dried oversodium sulfate, filtered and concentrated in vacuo to provide 0.4 g(92%) of the title compound as a white solid. MS (m/e): 352.4 (M+H).

c) Step 3 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-methoxynicotinicacid

To a solution of tert-butyl4-(6-methoxy-5-(methoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate(0.38 g, 1.1 mmol) in methanol (5 ml) was added 6 N sodium hydroxide(0.36 ml, 2.2 mmol) and the reaction heated to 80° C. for 16 h. Thereaction was concentrated to dryness, 5% aqueous citric acid was addedand the resulting precipitate isolated by filtration, affording 0.31 g(86%) of the title compound as a white solid. MS (m/e): 338.3 (M+H).

Example C.16 Preparation of6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluoronicotinic acid

To a suspension of tert-butyl4-(6-fluoro-5-(methoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate(0.1 g, 0.3 mmol)—Example C.15 (step 1) in tert-butanol (2 ml) was added6 N sodium hydroxide (0.1 ml, 0.6 mmol) and the mixture heated to 100°C. for 3 h. The reaction was concentrated to dryness, 5% aqueous citricacid was added and the resulting precipitate isolated by filtration,affording 0.08 g (87%) of the title compound as a white solid. MS (m/e):326.4 (M+H).

Example C.17 Preparation of6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-fluoronicotinic acid

a) Step 1 tert-butyl 4-(4-fluoropyridin-2-yl)piperazine-1-carboxylate

In analogy to the procedure described for the synthesis of example C.1(step 1), the title compound was prepared from 2-chloro-4-fluoropyridineand (tert-butyl piperazine-1-carboxylate. MS (m/e): 282.5 (M+H).

b) Step 2 tert-butyl4-(4-fluoro-5-iodopyridin-2-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(4-fluoropyridin-2-yl)piperazine-1-carboxylate (67 mg, 0.2 mmol) inDMF (0.5 ml) was added N-iodo-succinamide (82 mg, 0.4 mmol) and themixture stirred for 24 h. The reaction was then diluted with water,extracted with ethyl acetate, the organic phase was washed with brine,dried over sodium sulfate, filtered and concentrated in vacuo. The crudeoil was purified with flash column chromatography on silica (Eluent:Heptane/ethyl acetate 0 to 30%) to provide 73 mg (75%) of the titlecompound as a light yellow solid. MS (m/e): 408.5 (M+H).

c) Step 3 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-fluoronicotinicacid

To an ice-cold suspension of tert-butyl4-(4-fluoro-5-iodopyridin-2-yl)piperazine-1-carboxylate (63 mg, 0.2mmol) in tetrahydrofuran (0.2 ml) under argon was addedisopropylmagnesium chloride lithium chloride complex (0.13 ml, 1.3 M inTHF, 0.2 mmol). The mixture was allowed to come to ambient temperatureand stirred for 45 minutes before carbon dioxide gas was bubbled intothe reaction. After 1 h the mixture was diluted with water, extractedwith ethyl acetate, the aqueous layer was then acidified with 5% aqueouscitric acid solution and re-extracted with ethyl acetate. The ethylacetate was then washed with brine, dried over sodium sulfate, filteredand concentrated in vacuo to provide 29 mg (58%) of the title compoundas an off-white foam. MS (m/e): 326.5 (M+H).

Example C.18 Preparation of6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-methoxynicotinic acid

In analogy to the procedure described for the synthesis of example C.17(steps: 1-3), the title compound was prepared from2-chloro-4-methoxypyridine. MS (m/e): 338.6 (M+H).

Example C.19 Preparation of6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-ethoxynicotinic acid

In analogy to the procedure described for the synthesis of example C.17(steps: 1-3), the title compound was prepared from2-chloro-4-ethoxypyridine. MS (m/e): 352.5 (M+H).

Example C.20 Preparation of6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-(2,2,2-trifluoroethoxy)nicotinicacid

a) Step 1 2-chloro-4-(2,2,2-trifluoroethoxy)pyridine

To a solution of 2-chloro-4-nitropyridine (0.5 g, 3.2 mmol) intetrahydrofuran (20 ml) was added 2,2,2-trifluoroethanol (0.25 ml, 3.5mmol) and potassium tert-butoxide (0.4 g, 3.5 mmol). The reactionmixture was stirred at 60° C. overnight in a sealed vessel. The reactionwas concentrated to dryness, the residue re-dissolved in ethyl acetate,washed with sodium hydrogen carbonate, brine, dried over sodium sulfate,filtered and concentrated in vacuo. The crude oil was purified withflash column chromatography on silica (Eluent: Heptane/ethyl acetate 0to 30%) to provide 0.6 g (91%) of the title compound as a colourlessliquid. MS (m/e): 212.2 (M+H).

b)6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-(2,2,2-trifluoroethoxy)nicotinicacid

In analogy to the procedure described for the synthesis of example C.17(steps: 1-3), the title compound was prepared from2-chloro-4-(2,2,2-trifluoroethoxy)pyridine. MS (m/e): 406.6 (M+H).

Example C.21 Preparation of6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-ethoxynicotinic acid

In analogy to the procedure described for the synthesis of example C.15(steps: 1-3), except that ethanol is used in place of methanol assolvent in step 2, afforded the title compound. MS (m/e): 352.5 (M+H).

Example C.22 Preparation of6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(2,2,2-trifluoroethoxy)nicotinicacid

In analogy to the procedure described for the synthesis of example C.15(steps: 1-3), except that 2,2,2-trifluoroethanol is used in place ofmethanol as solvent in step 2, afforded the title compound. MS (m/e):404.7 (M−H).

Example C.23 Preparation ofrac-6-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)-2-methoxynicotinicacid

In analogy to the procedure described for the synthesis of example C.15(steps: 1-3), the title compound was prepared from rac-tert-butyl2-methylpiperazine-1-carboxylate and methyl 2,6-difluoronicotinate. MS(m/e): 350.5 (M−H).

Example C.24 Preparation of6-(4-(tert-butoxycarbonyl)-3,3-dimethylpiperazin-1-yl)-2-methoxynicotinicacid

In analogy to the procedure described for the synthesis of example C.15(steps: 1-3), the title compound was prepared from2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester and methyl2,6-difluoronicotinate. MS (m/e): 364.5 (M−H).

Example C.25 Preparation ofrac-6-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)-4-methoxynicotinicacid

In analogy to the procedure described for the synthesis of example C.18,the title compound was prepared from rac-tert-butyl2-methylpiperazine-1-carboxylate and 2-chloro-4-methoxypyridine. MS(m/e): 352.5 (M+H).

DESCRIPTION OF EXAMPLES Example 1 Preparation ofN-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(piperazin-1-yl)benzamide

To a solution ofN-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-fluorobenzamide (ExampleA. 1) (20 mg, 70.4 μmol) in N,N-dimethylacetamide (200 μl) undernitrogen at room temperature, was added piperazine (60.6 mg, 704 μmol).The reaction mixture was microwaved at 160° C. for 90 minutes. Themixture was cooled to room temperature. The resulting precipitate wasfiltered, rinsed with diethyl ether and dried to provide 4 mg (16.2%) ofthe title as an off-white solid. MS (m/e): 351.4 (M+H+)

In analogy to Example 1, compounds 2 to 30 of the following table wereprepared by reacting an halo-substituted amide derivative with anamino-substituted derivative at the indicated temperature:

MW Example found No. Structure Systematic Name Starting materials T (°C.) (MH⁺)  2

rac-N-(6,8- dimethylimidazo[1,2- a]pyrazin-2-yl)- 4-(3-methylpiperazin-1- yl)benzamide N-(6,8- dimethylimidazo[1,2-a]pyrazin-2-yl)-4- fluorobenzamide (Example A.1) and rac-2-methylpiperazine (commercial) 160 365.5  3

N-(6,8-Dimethyl- imidazo[1,2- a]pyrazin-2-yl)-4- ((S)-3-methyl-piperazin-1-yl)- benzamide N-(6,8- dimethylimidazo[1,2-a]pyrazin-2-yl)-4- fluorobenzamide (Example A.1) and (S)-(+)-2-methylpiperazine (commercial) 200 365.5  4

N-(6,8- dimethylimidazo[1,2- a]pyrazin-2-yl)- 2-fluoro-4-(4-methylpiperazin-1- yl)benzamide N-(6,8- dimethylimidazo[1,2-a]pyrazin-2-yl)-2,4- difluorobenzamide (Example A2) and 1-methylpiperazine (commercial) 180 383.5  5

rac-N-(6,8- dimethylimidazo[1,2- a]pyrazin-2-yl)- 2-fluoro-4-(3-methylpiperazin-1- yl)benzamide N-(6,8- dimethylimidazo[1,2-a]pyrazin-2-yl)-2,4- difluorobenzamide (Example A2) and rac-2-methylpiperazine (commercial) 180 383.5  6

N-(6,8- dimethylimidazo[1,2- a]pyrazin-2-yl)- 6-(4- methylpiperazin-1-yl)nicotinamide 6-chloro-N-(6,8- dimethylimidazo[1,2- a]pyrazin-2-yl)nicotinamide (Example A3) and 1- methylpiperazine (commercial) 120366.5  7

rac-N-(6,8- dimethylimidazo[1,2- a]pyrazin-2-yl)- 6-(3-methylpiperazin-1- yl)nicotinamide 6-chloro-N-(6,8- dimethylimidazo[1,2-a]pyrazin-2- yl)nicotinamide (Example A3) and rac-2- methylpiperazine(commercial) 180 366.5  8

N-(6,8- dimethylimidazo[1,2- a]pyrazin-2-yl)- 6-(4- ethylpiperazin-1-yl)nicotinamide 6-chloro-N-(6,8- dimethylimidazo[1,2- a]pyrazin-2-yl)nicotinamide (Example A3) and 1- ethylpiperazine (commercial) 130380.5  9

N-(6,8- dimethylimidazo[1,2- a]pyrazin-2-yl)- 5-(4- methylpiperazin-1-yl)picolinamide N-(6,8- dimethylimidazo[1,2- a]pyrazin-2-yl)-5-fluoropicolinamide (Example A4) and 1- methylpiperazine (commercial) 160366.5 10

rac-N-(6,8- dimethylimidazo[1,2- a]pyrazin-2-yl)- 5-(3-methylpiperazin-1- yl)picolinamide N-(6,8- dimethylimidazo[1,2-a]pyrazin-2-yl)-5- fluoropicolinamide (Example A4) and rac-2-methylpiperazine (commercial) 160 366.5 11

N-(6,8- dimethylimidazo[1,2- a]pyrazin-2-yl)- 5-(piperazin-1-yl)picolinamide N-(6,8- dimethylimidazo[1,2- a]pyrazin-2-yl)-5-fluoropicolinamide (Example A4) and piperazine (commercial) 160 352.5 12

rac-N-(2- methylimidazo[1,2- a]pyridin-6-yl)-6- (3- methylpiperazin-1-yl)nicotinamide 6-chloro-N-(2- methylimidazo[1,2- a]pyridin-6-yl)nicotinamide (Example A5) and rac-2- methylpiperazine (commercial)130 351.4 13

6-(3,3- dimethylpiperazin- 1-yl)-N-(2- methylimidazo[1,2- a]pyridin-6-yl)nicotinamide 6-chloro-N-(2- methylimidazo[1,2- a]pyridin-6-yl)nicotinamide (Example A5) and 2,2-Dimethyl- piperazine (commercial)130 365.5 14

N-(2- methylimidazo[1,2- a]pyridin-6-yl)-6- (piperazin-1-yl)nicotinamide 6-chloro-N-(2- methylimidazo[1,2- a]pyridin-6-yl)nicotinamide (Example A5) and piperazine (commercial) 130 337.5 15

6- hexahydropyrrolo [3,4-c]pyrrol-2(1H)- yl)-N-(2- methylimidazo[1,2-a]pyridin-6- yl)nicotinamide hydrochloride 6-chloro-N-(2-methylimidazo[1,2- a]pyridin-6- yl)nicotinamide (Example A5) andhexahydro- pyrrolo[3,4-c]pyrrole- 2-carboxylic acid tert-butylester(commercial) followed by treatment with HCl 130 363.5 16

N-(2- methylimidazo[1,2- a]pyridin-6-yl)-6- (2,6- diazaspiro[3.3]heptan-2- yl)nicotinamide hydrochloride 6-chloro-N-(2-methylimidazo[1,2- a]pyridin-6- yl)nicotinamide (Example A5) and2,6-Diaza- spiro[3.3]heptane-2- carboxylic acid tert- butyl ester(commercial) followed by treatment with HCl 130 349.5 17

rac-N-(2- methylimidazo[1,2- a]pyridin-6-yl)-5- (3- methylpiperazin-1-yl)picolinamide 5- fluoro-N-(2- methylimidazo[1,2- a]pyridin-6-yl)picolinamide (Example A6) and rac-2- methylpiperazine (commercial)160 351.5 18

rac-2-fluoro-N-(2- methylimidazo[1,2- a]pyridin-6-yl)-4- (3-methylpiperazin-1- yl)benzamide 2,4-difluoro-N-(2- methylimidazo[1,2-a]pyridin-6- yl)benzamide (Example A7) and rac-2- methylpiperazine(commercial) 100 368.5 19

N-(2-methyl-8- (trifluoromethyl) imidazo[1,2- a]pyridin-6-yl)-6-(piperazin-1- yl)nicotinamide 6-Chloro-N-(2- methyl-8- tritluoromethyl-imidazo[1,2-a]pyridin- 6-yl)-nicotinamide (Example A8) and piperazine(commercial) 130 405.4 20

rac-N-(2-methyl-8- (trifluoromethyl) imidazo[1,2- a]pyridin-6-yl)-6- (3-methylpiperazin-1- yl)nicotinamide 6-Chloro-N-(2- methyl-8-trifluoromethyl- imidazo[1,2-a]pyridin- 6-yl)-nicotinamide (Example A8)and rac-2- methylpiperazine (commercial) 130 419.4 21

(S)-6- (hexahydropyrrolo [1,2-a]pyrazin- 2(1H)-yl)-N-(2- methyl-8-(trifluoromethyl) imidazo[1,2- a]pyridin-6- yl)nicotinamide6-Chloro-N-(2- methyl-8- trifluoromethyl- imidazo[1,2-a]pyridin-6-yl)-nicotinamide (Example A8) and (S)- octahydropyrrolo[1,2-a]pyrazine (commercial) 130 445.7 22

6-(3,5- dimethylpiperazin- 1-yl)-N-(2-methyl- 8- (trifluoromethyl)imidazo[1,2- a]pyridin-6- yl)nicotinamide 6-Chloro-N-(2- methyl-8-trifluoromethyl- imidazo[1,2-a]pyridin- 6-yl)-nicotinamide (Example A8)and 2,6- dimethylpiperazine 130 433.7 23

6-(3,5- dimethylpiperazin- 1-yl)-N-(4-fluoro- 2- methylbenzo[d]oxazol-6- yl)nicotinamide 6-chloro-N-(4-fluoro- 2- methylbenzo[d]oxazol-6-yl)nicotinamide (Example A9) and 2,6- dimethylpiperazine 130 384.6 24

N-(4-fluoro-2- methylbenzo[d] oxazol-6-yl)-6-(4- methylpiperazin-1-yl)nicotinamide 6-chloro-N-(4-fluoro- 2- methylbenzo[d]oxazol-6-yl)nicotinamide (Example A9) and 1- methylpiperazine (commercial) 130370.6 25

(S)-N-(4-fluoro-2- methylbenzo[d] oxazol-6-yl)-6- (hexahydropyrrolo[1,2-a]pyrazin- 2(1H)- yl)nicotinamide 6-chloro-N-(4-fluoro-2-methylbenzo[d] oxazol-6- yl)nicotinamide (Example A9) and (S)-octahydropyrrolo[1,2- a]pyrazine (commercial) 130 396.6 26

N-(4-Fluoro-2- methyl- benzooxazol-6-yl)- 6-piperazin-1-yl- nicotinamide6-chloro-N-(4-fluoro- 2-methylbenzo[d] oxazol-6- yl)nicotinamide(Example A9) and piperazine (commercial) 130 356.6 27

rac-N-(4-Fluoro-2- methyl- benzooxazol-6-yl)- 6-(3-methyl-piperazin-1-yl)- nicotinamide 6-chloro-N-(4-fluoro- 2- methylbenzo[d]oxazol-6- yl)nicotinamide (Example A9) and rac-2- methylpiperazine(commercial) 130 370.6 28

N-(4-fluoro-2- methylbenzo[d] oxazol-6-yl)-4- (piperazin-1- yl)benzamide4-fluoro-N-(4-fluoro- 2-methylbenzo[d] oxazol-6-yl)benzamide (ExampleA10) and piperazine (commercial) 160 355.6 29

rac-N-(4-fluoro-2- methylbenzo[d] oxazol-6-yl)-4-(3- methylpiperazin-1-yl)benzamide 4-fluoro-N-(4-fluoro- methylbenzo[d]oxazol- 6-yl)benzamide(Example A10) and rac-2- methylpiperazine (commercial) 160 369.6 30

4-(3,5- dimethylpiperazin- 1-yl)-N-(4-fluoro- 2-methylbenzo[d] oxazol-6-yl)benzamide 4-fluoro-N-(4-fluoro- 2- methylbenzo[d]oxazol-6-yl)benzamide (Example A10) and 2,6- dimethylpiperazine 160383.7

Example 31(S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)benzamide

To a solution of(S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzoic acid(Example C.1) (80 mg, 303 μmol) in N,N-dimethylformamide (800 μl) undernitrogen at room temperature, were added HATU(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate) (173 mg, 454 μmol) and N-ethyldiisopropylamine (156mg, 206 μl, 1.21 mmol). After 5 minutes stirring at room temperature,2-methylimidazo[1,2-a]pyridin-6-amine hydrobromide (commercial) (69.0mg, 303 μmol) was added. The mixture was shaked at 60° C. for 5.5 hoursand then at room temperature for two days. The solvent was removed invacuo. The residue was taken in a saturated aqueous solution ofbicarbonate. Ethyl acetate was added. The resulting precipitate wasfiltered, rinsed with ethyl acetate and dried. The solid was stirred inethyl acetate, filtered, rinsed with cold ethyl acetate and n-hexane anddried to provide 11 mg (9%) of the title compound as a light brownsolid. MS (m/e): 394.6 (M+H)

In analogy to Example 31, compounds 32 to 35 of the following table wereprepared from the acid and amine derivatives:

MW Expl. found No. Structure Systematic Name Starting materials (MH⁺) 32

N-(8-fluoro-2- methylimidazo[1,2- a]pyridin-6-yl)-6-(4-methylpiperazin-1- yl)nicotinamide 6-(4-Methyl-piperazin-1-yl)-nicotinic acid (commercial) and 8-Fluoro- 2-methyl-imidazo[1,2-a]pyridin-6-ylamine hydrochloride (Example B.4) 369.5 33

(S)-2-Fluoro-N-(4- fluoro-2-methyl- benzooxazol-6-yl)-4- (S)-hexahydro-pyrrolo[1,2-a]pyrazin- 2-yl-benzamide (S)-2-fluoro-4-(hexahydropyrrolo[1,2- a]pyrazin-2(1H)-yl)benzoic acid (Example C.1) and4- fluoro-2- methylbenzo[d]oxazol-6- amine hydrochloride (Example B.3)413.7 34

(R)-2-fluoro-N-(4- fluoro-2- methylbenzo[d]oxazol- 6-yl)-4-(hexahydropyrrolo[1,2- a]pyrazin-2(1H)- yl)benzamide (R)-2-fluoro-4-(hexahydropyrrolo[1,2- a]pyrazin-2(1H)-yl)benzoic acid (Example C.2) and4- fluoro-2- methylbenzo[d]oxazol-6- amine hydrochloride (Example B.3)413.6 35

(S)-2-fluoro-4- (hexahydropyrrolo[1,2- a]pyrazin-2(1H)-yl)-N-(2-methyl-8- (trifluoromethyl) imidazo[1,2- a]pyridin-6- yl)benzamide(S)-2-fluoro-4- (hexahydropyrrolo[1,2- a]pyrazin-2(1H)-yl)benzoic acid(Example C.1) and 2- Methyl-8-trifluoromethyl- imidazo[1,2-a]pyridin-6-ylamine hydrochloride (Example B.2) 462.5

Example 36 Preparation ofN-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzamidehydrochloride

To a solution of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid(commercial) (109 mg, 357 μmol) in N,N-dimethylformamide (1.00 ml) undernitrogen at room temperature, were added HATU(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate) (204 mg, 536 μmol) and N-ethyldiisopropylamine (185mg, 243 μl, 1.43 mmol). After 5 minutes stirring at room temperature,8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-ylamine hydrochloride (ExampleB.4) (72 mg, 357 μmol) was added. The mixture was stirred at roomtemperature for 21 hours and then at 60° C. for 2 hours. The solvent wasremoved in vacuo. The residue was taken in a saturated aqueous solutionof bicarbonate and extracted three times with ethyl acetate. Thecombined extracts were dried over sodium sulfate, filtered andconcentrated in vacuo. The crude oil was purified on silica gel (Eluent:heptane/ethyl acetate 0 to 10%) to provide 78 mg of tert-butyl4-(4-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-ylcarbamoyl)phenyl)piperazine-1-carboxylate.To a suspension of this compound (40 mg, 88.2 μmol) in methanol (400 μl)was added HCl 4M in dioxane (221 μl, 882 μmol). The light yellowsuspension was stirred at room temperature for 17 hours. The solid wasfiltered, washed with ether and hexane and dried to provide 25 mg(72.7%) of the title compound as a light yellow solid. MS(m/e): 354.5(M+H).

In analogy to Example 36, compounds 37 to 63 of the following table wereprepared from the acid and amine derivatives followed by treatment withHCl or TFA.

MW Expl. found No. Structure Systematic Name Starting materials (MH⁺) 37

rac-N-(2,8- dimethylimidazo[1,2- a]pyridin-6-yl)-2- fluoro-4-(3-methylpiperazin-1- yl)benzamide dihydrochloride4-(4-(tert-butoxycarbonyl)- 3-methylpiperazin-1-yl)-2- fluorobenzoicacid (Example C.3) and 2,8- dimethylimidazo[1,2- a]pyridin-6-aminehydrochloride (CAS: 1216295-25-8) followed by treatment with HCl 382.638

rac-2-fluoro-N-(2- methylbenzo[d]oxazol- 6-yl)-4-(3- methylpiperazin-1-yl)benzamide dihydrochloride 4-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)-2- fluorobenzoic acid (Example C.3) and 2-Methyl-benzooxazol-6- ylamine (commercial) followed by treatment withHCl 369.5 39

rac-2-fluoro-N-(8- fluoro-2- methylimidazo[1,2- a]pyridin-6-yl)-4-(3-methylpiperazin-1- yl)benzamide dihydrochloride 4-(4-(tert-butoxycarbonyl)- 3-methylpiperazin-1-yl)-2- fluorobenzoic acid(Example C.3) and 8- Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylaminehydrochloride (Example B.4) followed by treatment with HCl 386.6 40

2-fluoro-N-(8-fluoro- 2-methylimidazo[1,2- a]pyridin-6-yl)-4-(piperazin-1- yl)benzamide dihydrochloride 4-(4-(tert-butoxycarbonyl)piperazin-1- yl)-2-fluorobenzoic acid (CAS: 1121596-45-9)and 8-Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylamine hydrochloride(Example B.4) followed by treatment with HCl 372.6 41

N-(8-fluoro-2- methylimidazo[1,2- a]pyridin-6-yl)-6- (piperazin-1-yl)nicotinamide dihydrochloride 4-(5-Carboxy-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (CAS: 201809-22-5) and8-Fluoro- 2-methyl-imidazo[1,2- a]pyridin-6-ylamine hydrochloride(Example B.4) followed by treatment with HCl 355.5 42

rac-N-(8-fluoro-2- methylimidazo[1,2- a]pyridin-6-yl)-6-(3-methylpiperazin-1- yl)nicotinamide dihydrochloride rac-6-(4-(tert-butoxycarbonyl)-3- methylpiperazin-1- yl)nicotinic acid (CAS:904817-70-5) and 8-Fluoro- 2-methyl-imidazo[1,2- a]pyridin-6-ylaminehydrochloride (Example B.4) followed by treatment with HCl 369.6 43

rac-N-(8-fluoro-2- methylimidazo[1,2- a]pyridin-6-yl)-5-(3-methylpiperazin-1- yl)picolinamide dihydrochloriderac-4-(6-Carboxy-pyridin-3- yl)-2-methyl-piperazine-1- carboxylic acidtert-butyl ester (Example C.4) and 8- Fluoro-2-methyl-imidazo[1,2-a]pyridin-6- ylamine hydrochloride (Example B.4) followed bytreatment with HCl 369.6 44

2-fluoro-N-(2- methylimidazo[1,2- a]pyridin-6-yl)-4- (piperazin-1-yl)benzamide hydrochloride 4-(4-(tert- butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid (CAS: 1121596-45-9) and 2-methylimidazo[1,2-a]pyridin-6-amine hydrobromide (commercial) followed by treatment withHCl 354.6 45

rac-2,3-difluoro-N-(8- fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1- yl)benzamide hydrochloriderac-4-(4-(tert- butoxycarbonyl)-3- methylpiperazin-1-yl)-2,3-difluorobenzoic acid (Example C.5) and 8- Fluoro-2-methyl-imidazo[1,2-a]pyridin-6- ylamine hydrochloride (Example B.4) followed bytreatment with HCl 404.6 46

rac-2,5-difluoro-N-(8- fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1- yl)benzamide hydrochloriderac-4-(4-Carboxy-2,5- difluoro-phenyl)-2-methyl- piperazine-1-carboxylicacid tert-butyl ester (Example C.6) and 8-Fluoro-2-methyl-imidazo[1,2-a]pyridin-6- ylamine hydrochloride (Example B.4) followed bytreatment with HCl 404.5 47

rac-5-fluoro-N-(8- fluoro-2- methylimidazo[1,2- a]pyridin-6-yl)-6-(3-methylpiperazin-1- yl)nicotinamide hydrochloride rac-6-(4-(tertbutoxycarbonyl)-3- methylpiperazin-1-yl)-5- fluoronicotinic acid(Example C.7) and 8- Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylaminehydrochloride (Example B.4) followed by treatment with HCl 387.5 48

rac-3-fluoro-N-(8- fluoro-2- methylimidazo[1,2- a]pyridin-6-yl)-5-(3-methylpiperazin-1- yl)picolinamide hydrochloride rac-5-(4-(tertbutoxycarbonyl)-3- methylpiperazin-1-yl)-3- fluoropicolinic acid(Example C.8) and 8- Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylaminehydrochloride (Example B.4) followed by treatment with HCl 387.6 49

rac-2,6-difluoro-N-(8- fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-4-(3- methylpiperazin-1- yl)benzamide hydrochloriderac-4-(4- (tertbutoxycarbonyl)-3- methylpiperazin-1-yl)-2,6-difluorobenzoic acid (Example C.9) and 8- Fluoro-2-methyl-imidazo[1,2-a]pyridin-6- ylamine hydrochloride (Example B.4) followed bytreatment with HCl 404.6 50

(S)-2-fluoro-N-(8- fluoro-2- methylimidazo[1,2- a]pyridin-6-yl)-4-(3-methylpiperazin-1- yl)benzamide hydrochloride (S)-4-(4-(tertbutoxycarbonyl)-3- methylpiperazin-1-yl)-2- fluorobenzoic acid(Example C.10) and 8- Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylaminehydrochloride (Example B.4) followed by treatment with HCl 386.6 51

(R)-2-fluoro-N-(8- fluoro-2- methylimidazo[1,2- a]pyridin-6-yl)-4-(3-methylpiperazin-1- yl)benzamide hydrochloride (R)-4-(4-(tertbutoxycarbonyl)-3- methylpiperazin-1-yl)-2- fluorobenzoic acid(Example C.11) and 8- Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylaminehydrochloride (Example B.4) followed by treatment with HCl 386.6 52

rac-N-(2,7- dimethylimidazo[1,2- a]pyridin-6-yl)-2- fluoro-4-(3-methylpiperazin-1- yl)benzamide dihydrochloride rac-4-(4-(tert-butoxycarbonyl)-3- methylpiperazin-1-yl)-2- fluorobenzoic acid (ExampleC.3) and 2,7- dimethylimidazo[1,2- a]pyridin-6-amine hydrochloride (CAS:1216109-27-1) followed by treatment with HCl 382.5 53

rac-N-(8-chloro-2- methylimidazo[1,2- a]pyridin-6-yl)-5- fluoro-6-(3-methylpiperazin-1- yl)nicotinamide hydrochloride rac-6-(4-(tertbutoxycarbonyl)-3- methylpiperazin-1-yl)-5- fluoronicotinic acid(Example C.7) and 8- chloro-2- methylimidazo[1,2- a]pyridin-6-aminehydrochloride (Example B.5) followed by treatment with HCl 403.5 54

rac-N-(8-chloro-2- methylimidazo[1,2- a]pyridin-6-yl)-2- fluoro-4-(3-methylpiperazin-1- yl)benzamide dihydrochloride rac-4-(4-(tert-butoxycarbonyl)-3- methylpiperazin-1-yl)-2- fluorobenzoic acid (ExampleC.3) and 8- chloro-2- methylimidazo[1,2- a]pyridin-6-amine hydrochloride(Example B.5) followed by treatment with HCl 402.5 55

rac-N-(8-chloro-2- methylimidazo[1,2- a]pyridin-6-yl)-6-(3-methylpiperazin-1- yl)nicotinamide dihydrochloride rac-6-(4-(tert-butoxycarbonyl)-3- methylpiperazin-1- yl)nicotinic acid (CAS:904817-70-5) and 8-chloro- 2-methylimidazo[1.2- a]pyridin-6-aminehydrochloride (Example B.5) followed by treatment with HCl 385.6 56

rac-N-(8-chloro-2- methylimidazo[1,2- a]pyridin-6-yl)-3- fluoro-5-(3-methylpiperazin-1- yl)picolinamide dihydrochloride rac-5-(4-(tertbutoxycarbonyl)-3- methylpiperazin-1-yl)-3- fluoropicolinic acid(Example C.8) and 8- chloro-2- methylimidazo[1,2- a]pyridin-6-aminehydrochloride (Example B.5) followed by treatment with HCl 403.5 57

rac-N-(8-chloro-2- methylimidazo[1,2- a]pyridin-6-yl)-2,6-difluoro-4-(3- methylpiperazin-1- yl)benzamide trihydrochloriderac-4-(4- (tertbutoxycarbonyl)-3- methylpiperazin-1-yl)-2,6-difluorobenzoic acid (Example C.9) and 8- chloro-2- methylimidazo[1,2-a]pyridin-6-amine hydrochloride (Example B.5) followed by treatment withHCl 420.5 58

2-fluoro-N-(4-fluoro- 2- methylbenzo[d]oxazol- 6-yl)-4-(piperazin-1-yl)benzamide 4-(4-(tert- butoxycarbonyl)piperazin-1- yl)-2-fluorobenzoicacid (CAS: 1121596-45-9) and 4-fluoro-2- methylbenzo[d]oxazol-6- aminehydrochloride (Example B.3) followed by treatment with TFA 373.5 59

2-fluoro-N-(2-methyl- 8-(trifluoromethyl) imidazo[1,2- a]pyridin-6-yl)-4-(piperazin-1- yl)benzamide 4-(4-(tert- butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid (CAS: 1121596-45-9) and2-Methyl-8-trifluoromethyl- imidazo[1,2-a]pyridin-6- ylaminehydrochloride (Example B.2) followed by treatment with TFA 422.5 60

2-fluoro-N-(2- methylimidazo[1,2- a]pyridin-6-yl)-4- (1,2,3,6-tetrahydropyridin-4- yl)benzamide hydrochloride4-(1-(tert-butoxycarbonyl)- 1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzoic acid (Example C.12) and 2- methylimidazo[1,2-a]pyridin-6-amine hydrobromide (commercial followed by treatment withHCl 351.5 61

2-fluoro-N-(8-fluoro- 2-methylimidazo[1,2- a]pyridin-6-yl)-4- (1,2,3,6-tetrahydropyridin-4- yl)benzamide hydrochloride4-(1-(tert-butoxycarbonyl)- 1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzoic acid (Example C.12) and 8- Fluoro-2-methyl-imidazo[1,2-a]pyridin-6- ylamine hydrochloride (Example B.4) followed bytreatment with HCl 369.5 62

N-(8-fluoro-2- methylimidazo[1,2- a]pyridin-6-yl)-6- (1,2,3,6-tetrahydropyridin-4- yl)nicotinamide dihydrochloride6-(1-(tert-butoxycarbonyl)- 1,2,3,6-tetrahydropyridin-4- yl)nicotinicacid (Example C.13) and 8-Fluoro-2- methyl-imidazo[1,2-a]pyridin-6-ylamine hydrochloride (Example B.4) followed by treatmentwith HCl 352.5 63

N-(2- methylimidazo[1.2- a]pyridin-6-yl)-5- (1,2,3,6-tetrahydropyridin-4- yl)picolinamide dihydrochloride5-(1-(tert-butoxycarbonyl)- 1,2,3,6-tetrahydropyridin-4- yl)picolinicacid (Example C.14) and 2- methylimidazo[1,2- a]pyridin-6-aminehydrobromide (commercial followed by treatment with HC1 334.5

Example 64 Preparation ofN-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(piperazin-1-yl)nicotinamide

To a solution of6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-methoxynicotinic acid(Example C.15) (100 mg, 296 μmol) and8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-ylamine hydrochloride (ExampleB.4) (60 mg, 296 μmol) in N,N-dimethylformamide (1.00 ml) under argon atroom temperature, was addedO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(114 mg, 536 μmol) and triethylamine (124 μl, 0.89 mmol). The mixturewas stirred at 55° C. for 16 hours and then at 90° C. for 3 hours. Thereaction was poured into water and extracted with ethyl acetate. Theethyl acetate was dried over sodium sulfate, filtered and concentratedin vacuo. The crude oil was purified on silica gel (Eluent:heptane/ethyl acetate 50 to 100%) to provide 76 mg of tert-butyl4-(5-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-ylcarbamoyl)-6-methoxypyridin-2-yl)piperazine-1-carboxylate.This compound was then dissolved in 4M HCl in dioxane (2 ml) and themixture stirred for 0.5 h. The mixture was evaporated to dryness invacuo, the residue dissolved in saturated sodium hydrogen carbonate andrepeatedly extracted with dichloromethane. The combined extracts weredried over sodium sulfate, filtered and concentrated in vacuo. dried toprovide 39 mg (63%) of the title compound as an off-white solid.MS(m/e): 385.4 (M+H).

In analogy to Example 64, compounds 65 to 76 of the following table wereprepared from the acid and amine derivatives followed by treatment withHCl

MW Expl. found No. Structure Systematic Name Starting materials (MH⁺) 65

2-fluoro-N-(8-fluoro- 2-methylimidazo[1,2- a]pyridin-6-yl)-6-(piperazin-1- yl)nicotinamide 6-(4-(tert- butoxycarbonyl)piperazin-1-yl)-2-fluoronicotinic acid (Example C.16) and 8- Fluoro-2-methyl-imidazo[1,2-a]pyridin-6- ylamine hydrochloride (Example B.4) followed bytreatment with HCl 373.3 66

N-(8-fluoro-2- methylimidazo[1,2- a]pyridin-6-yl)-3-methyl-4-(piperazin-1- yl)benzamide 4-(4-(tert-butoxycarbonyl)piperazin-1- yl)-3-methylbenzoic acid (CAS: 196203-51-7)and 8- Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylamine hydrochloride(Example B.4) followed by treatment with HCl 368.6 67

N-(8-fluoro-2- methylimidazo[1,2- a]pyridin-6-yl)-5-methyl-6-(piperazin-1- yl)nicotinamide 6-(4-(tert-butoxycarbonyl)piperazin-1- yl)-5-methylnicotinic acid (CAS:1211527-14-8) and 8-Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylaminehydrochloride (Example B.4) followed by treatment with HCl LG 68

4-fluoro-N-(8-fluoro- 2-methylimidazo[1,2- a]pyridin-6-yl)-6-(piperazin-1- yl)nicotinamide 6-(4-(tert- butoxycarbonyl)piperazin-1-yl)-4-fluoronicotinic acid (Example C.17) and 8- Fluoro-2-methyl-imidazo[1,2-a]pyridin-6- ylamine hydrochloride (Example B.4) followed bytreatment with HCl 373.7 69

N-(8-fluoro-2- methylimidazo[1,2- a]pyridin-6-yl)-4-methoxy-6-(piperazin- 1-yl)nicotinamide 6-(4-(tert-butoxycarbonyl)piperazin-1- yl)-4-methoxynicotinic acid (Example C.18)and 8- Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylamine hydrochloride(Example B.4) followed by treatment with HCl 385.6 70

4-ethoxy-N-(8-fluoro- 2-methylimidazo[1,2- a]pyridin-6-yl)-6-(piperazin-1- yl)nicotinamide 6-(4-(tert- butoxycarbonyl)piperazin-1-yl)-4-ethoxynicotinic acid (Example C.19) and 8- Fluoro-2-methyl-imidazo[1,2-a]pyridin-6- ylamine hydrochloride (Example B.4) followed bytreatment with HCl 399.6 71

N-(8-fluoro-2- methylimidazo[1,2- a]pyridin-6-yl)-6- (piperazin-1-yl)-4-(2,2,2- trifluoroethoxy) nicotinamide 6-(4-(tert-butoxycarbonyl)piperazin-1- yl)-4-(2,2,2- trifluoroethoxy)nicotinicacid(Example C.20) and 8- Fluoro-2-methyl- imidazo[1,2-a]pyridin-6-ylamine hydrochloride (Example B.4) followed by treatment with HCl 453.6[ 72

2-ethoxy-N-(8-fluoro- 2-methylimidazo[1,2- a]pyridin-6-yl)-6-(piperazin-1- yl)nicotinamide 6-(4-(tert- butoxycarbonyl)piperazin-1-yl)-2-ethoxynicotinic acid (Example C.21) and 8- Fluoro-2-methyl-imidazo[1,2-a]pyridin-6- ylamine hydrochloride (Example B.4) followed bytreatment with HCl 399.6 73

N-(8-fluoro-2- methylimidazo[1,2- a]pyridin-6-yl)-6- (piperazin-1-yl)-2-(2,2,2- trifluoroethoxy) nicotinamide 6-(4-(tert-butoxycarbonyl)piperazin-1- yl)-2-(2,2,2- trifluoroethoxy)nicotinic acid(Example C.22) and 8- Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylaminehydrochloride (Example B.4) followed by treatment with HCl 453.6 74

rac-N-(8-fluoro-2- methylimidazo[1,2- a]pyridin-6-yl)-2- methoxy-6-(3-methylpiperazin-1- yl)nicotinamide rac-6-(4-(tert- butoxycarbonyl)-3-methylpiperazin-1-yl)-2- methoxynicotinic acid (Example C.23) and 8-Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylamine hydrochloride (ExampleB.4) followed by treatment with HCl 399.6 75

6-(3,3- dimethylpiperazin-1- yl)-N-(8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)-2- methoxynicotinamide 6-(4-(tert-butoxycarbonyl)-3,3-dimethylpiperazin-1-yl)- 2-methoxynicotinic acid (Example C.24) and8- Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylamine hydrochloride(Example B.4) followed by treatment with HCl 411.6 76

rac-N-(8-fluoro-2- methylimidazo[1,2- a]pyridin-6-yl)-4- methoxy-6-(3-methylpiperazin-1- yl)nicotinamide 6-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)-4- methoxynicotinic acid (Example C.25) and 8-Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylamine hydrochloride (ExampleB.4) followed by treatment with HCl 399.5

Example 77 Preparation ofN-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)nicotinamidehydrochloride

a) Step 1 tert-butyl4-(5-(2-methylimidazo[1,2-a]pyridin-6-ylcarbamoyl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate

To a solution of6-chloro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nicotinamide (Example A5)(100 mg, 349 μmol) in a mixture of 1,2-dimethoxyethane (1.25 ml),ethanol (625 μl) and water (1.25 ml) under nitrogen at room temperature,were added tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(129 mg, 419 μmol), K2CO3 (122 mg, 875 μmol) and PdCl2(Ph3P)2 (25.2 mg,35.9 μmol, Eq: 0.103). The reaction mixture was heated in an oil bath at100° C. for 40 minutes. After cooling to room temperature, the solventwas removed under reduced pressure. The residue was dissolved indichloromethane and washed with brine. The aqueous phase was extractedthree times with methylene chloride and the combined organic phase wasdried with Na2SO4, filtered and concentrated to dryness to obtain 285 mgof a dark brown solid. This solid was suspended in ethyl acetate,filtered and dried to provide 86 mg (56.9%) of the title compound as alight brown solid. MS (m/e): 434.5 (M+H+).

b) Step 2N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)nicotinamidehydrochloride

To a solution of tert-butyl4-(5-(2-methylimidazo[1,2-a]pyridin-6-ylcarbamoyl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(20 mg, 46.1 μmol) in methanol (200 μl) under nitrogene at roomtemperature, was added dropwise hydrogen chloride (4M in dioxane) (115μl, 461 μmol). The reaction mixture was stirred at room temperatureovernight. The resulting precipitation was filtered, rinsed with diethylether and dried to provide 12.6 mg (73.8%) of the expected compound as agrey solid. MS(m/e): 334.5 (M+H+).

Example 78 Preparation ofN-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl)nicotinamide

a) Step 1 tert-butyl4-(5-(2-methylimidazo[1,2-a]pyridin-6-ylcarbamoyl)pyridin-2-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-(5-(2-methylimidazo[1,2-a]pyridin-6-ylcarbamoyl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(Example 77, step 1) (123 mg, 284 μmol) in methanol (7 ml) andtetrahydrofurane (3.5 ml) under nitrogen at room temperature was addedpalladium on activated charcoal (54.3 mg, 51.0 μmol). The reactionmixture was stirred under a hydrogen atmosphere overnight. The reactionmixture was purged with argon, filtered and the solvent was evaporated.The crude oil was purified with flash column chromatography on silicaeluting with a gradient formed from n-heptane and ethyl acetate (0 to100%) and ethyl acetate and methanol (0 to 15%) to provide 86 mg (69.6%)of the title compound as an off-white solid. MS (m/e): 436.6 (M+H)

b) Step 2N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperidin-4-yl)nicotinamide

To a suspension of tert-butyl4-(5-(2-methylimidazo[1,2-a]pyridin-6-ylcarbamoyl)pyridin-2-yl)piperidine-1-carboxylate(17 mg, 39.0 μmol) in methanol (170 μl) was added HCl 4M in dioxane(97.6 μl, 390 μmol). The light yellow solution was stirred at roomtemperature overnight. The solvent was evaporated to provide 14 mg(87.8%) of the title compound as a grey solid. MS(m/e): 336.3 (M+H)

c) Step 3N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl)nicotinamide

To a suspension ofN-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperidin-4-yl)nicotinamide(25 mg, 74.5 μmol) in 1,2-dichloroethane (250 μl) under nitrogene at5-10° C., was added sodium triacetoxyborohydride (26.3 mg, 112 μmol),followed dropwise (over 5 minutes) by formaldehyde solution (37% inwater) (18.1 mg, 16.6 μl, 224 μmol). The temperature was kept to 5-10°C. and the reaction mixture was stirred for 40 minutes. The reaction wasquenched with a 2N sodium carbonate aqueous solution. The resultingprecipitation was stirred at room temperature for 30 minutes, filtered,rinsed and dried to provide 17 mg (65.3%) of the title compound as anoff-white solid. MS(m/e): 350.5 (M+H+)

Example 79 Preparation ofN-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperidin-4-yl)nicotinamidedihydrochloride

To a solution ofN-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)nicotinamidedihydrochloride (Example 62) (30 mg, 70.7 μmol) in methanol (1.7 ml) andtetrahydrofurane (850 μl) under nitrogen at room temperature, was addedpalladium on activated charcoal (20 mg, 18.8 μmol, Eq: 0.266). Thereaction mixture was stirred under a hydrogen atmosphere for 4 hours.The reaction mixture was purged with argon, filtered and the solvent wasevaporated to provide 28 mg (92.9%) of the title compound as a yellowsolid. MS (m/e): 354.5 (M+H+).

Example 80 Preparation ofN-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl)nicotinamide

In analogy to the procedure described for the synthesis of example 78(steps: 3), the title compound was prepared fromN-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperidin-4-yl)nicotinamidedihydrochloride (Example 79). MS (m/e): 368.5 (M+H+).

Example 81 Preparation of2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperidin-4-yl)benzamidehydrochloride

In analogy to the procedure described for the synthesis of example 79,the title compound was prepared from2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide(Example 61). MS (m/e): 371.5 (M+H+).

Example 82 Preparation ofrac-6-(3,4-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nicotinamide

In analogy to the procedure described for the synthesis of example 78(step 3), the title compound was prepared fromrac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide(Example 12). MS (m/e): 365.6 (M+H+).

Biological Assays

To describe in more detail and assist in understanding the presentdescription, the following non-limiting biological examples are offeredto more fully illustrate the scope of the description and are not to beconstrued as specifically limiting the scope thereof. Such variations ofthe present description that may be now known or later developed, whichwould be within the purview of one skilled in the art to ascertain, areconsidered to fall within the scope of the present description and ashereinafter claimed. These examples illustrate the testing of certaincompounds described herein in vitro and/or in vivo and demonstrate theusefulness of the compounds for treating of SMA by enhancing theinclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene.Compounds of formula (I) enhance inclusion of exon 7 of SMN2 into mRNAtranscribed from the SMN2 gene and increase levels of SMN proteinproduced from the SMN2 gene, and thus can be used to treat SMA in ahuman subject in need thereof. These examples further illustrate thetesting of certain compounds described herein in vitro and/or in vivoand demonstrate the usefulness of the compounds for enhancing theinclusion of exon 7 of SMNI into mRNA transcribed from the SMN1 gene.Accordingly, compounds of formula (I) also enhance the inclusion of exon7 of SMN1 into mRNA transcribed from the SMN1 gene and increase levelsof SMN protein produced from the SMN1 gene.

Example D.1 SMN2 Minigene mRNA Splicing RT-qPCR Assay in Cultured Cells

The reverse transcription-quantitative PCR-based (RT-qPCR) assay is usedto quantify the level of the full length SMN2 minigene (referred toherein by the term “FL SMN2mini”) mRNA containing SMN2 exon 7 in aHEK293H cell line stably transfected with said minigene and treated witha test compound.

Material Source HEK293H cells Life Technologies, Inc. (formerlyInvitrogen) Catalog No. 11631-017 Cells-To-Ct lysis Life Technologies,Inc. (formerly Applied buffer Biosystems) part No. 4399002 DMEM LifeTechnologies, Inc. (formerly Invitrogen) Catalog No. 11960-044 96-wellflat-bottom Becton Dickinson Catalog No. 353072 plates RT-PCR EnzymeLife Technologies, Inc. (formerly Applied Mix Biosystems) part No.4388520 RT-PCR buffer Life Technologies, Inc. (formerly AppliedBiosystems) part No. 4388519 AgPath-ID One- Life Technologies, Inc.(formerly Applied Step RT-PCR kit Biosystems) part No. 4387391Thermocycler Life Technologies, Inc. (formerly Applied Biosystems)7900HT

The SMN2-A minigene construct was prepared as described in InternationalPatent Application WO2009/151546A1 page 145 paragraph [00400] to page147 paragraph [00412] (incl. FIG. 1 and FIG. 3 therein).

HEK293H cells stably transfected with the SMN2-A minigene construct(10,000 cells/well) are seeded in 200 μL of cell culture medium (DMEMplus 10% FBS, with 200 g/mL hygromycin) in 96-well flat-bottom platesand the plate is immediately swirled to ensure proper dispersal of cellsand the formation of an even monolayer of cells. Cells are allowed toattach for 6 hours. Test compounds are serially diluted 3.16-fold in100% DMSO to generate a 7-point concentration curve. A solution of testcompound (1 μL, 200× in DMSO) is added to each cell-containing well andthe plate is incubated for 24 hours in a cell culture incubator (37° C.,5% C0₂, 100% relative humidity). 2 replicates are prepared for each testcompound concentration. The cells are then lysed in the Cells-To-Ctlysis buffer and the lysate is stored at −80° C.

Full length SMN2-A minigene and GAPDH mRNA are quantified using theprimers and probes referenced in Table 1. Primer SMN Forward A (SEQ IDNO.1) hybridizes to a nucleotide sequence in exon 7 (nucleotide 22 tonucleotide 40), primer SMN Reverse A (SEQ ID NO.2) hybridizes to anucleotide sequence in the coding sequence of Firefly luciferase, SMNProbe A (SEQ ID NO.3) hybridizes to a nucleotide sequence in exon 7(nucleotide 50 to nucleotide 54) and exon 8 (nucleotide 1 to nucleotide21). The combination of these three oligonucleotides detects only SMN1or SMN2 minigenes (RT-qPCR) and will not detect endogenous SMN1 or SMN2genes.

TABLE 1 Primers/Probes Sequences Source SMN ForwardSEQ ID NO.1: GAAGGAAGGTGCTCA PTC¹ Primer A CATT SMN ReverseSEQ ID NO.2: TCTTTATGTTTTTGG PTC¹ Primer A CGTCTTC SMN ForwardSEQ ID NO.3: 6FAM-AAGGAGAAAT PTC¹ Probe A GCTGGCATAGAGCAGC-TAMRAhGAPDH Forward SEQ ID NO.4: VIC-CGCCTGGTCAC LTI² Probe CAGGGCTGCT-TAMRAhGAPDH Forward SEQ ID NO.5: CAACGGATTTGGTCG LTI² Primer TATTGGhGAPDH Reverse SEQ ID NO.6: TGATGGCAACAATAT LTI² Primer CCACTTTACC¹Primers and probes designed by PTC Therapeutics, Inc.; ²Commerciallyavailable from Life Technologies, Inc. (formerly Invitrogen).

The SMN forward and reverse primers are used at final concentrations of0.4 μM. The SMN probe is used at a final concentration of 0.15 μM. TheGAPDH primers are used at final concentrations of 0.2 μM and the probeat 0.15 μM.

The SMN2-minigene GAPDH mix (15 μL total volume) is prepared bycombining 7.5 μL of 2×RT-PCR buffer, 0.4 μL of 25×RT-PCR enzyme mix,0.75 μL of 20×GAPDH primer-probe mix, 4.0075 μL of water, 2 μL of10-fold diluted cell lysate, 0.06 μL of 100 μM SMN forward primer, 0.06μL of 100 μM SMN reverse primer, and 0.225 μL of 100 μM SMN probe.

PCR is carried out at the following temperatures for the indicated time:Step 1: 48° C. (15 min); Step 2: 95° C. (10 min); Step 3: 95° C. (15sec); Step 4: 60° C. (1 min); then repeat Steps 3 and 4 for a total of40 cycles.

Each reaction mixture contains both SMN2-A minigene and GAPDHprimers/probe sets (multiplex design), allowing simultaneous measurementof the levels of two transcripts.

The increase in the abundance of the FL SMN2mini mRNA relative to thatin cells treated with vehicle control is determined from real-time PCRdata using a modified ΔΔCt method (as described in Livak and Schmittgen,Methods, 2001, 25:402-8). The amplification efficiency E is calculatedfrom the slope of the amplification curve for FL SMN2mini and GAPDHindividually. The abundance of FL SMN2mini and GAPDH mRNA are thencalculated as (1+E)^(−Ct), where Ct is the threshold value for eachamplicon. The abundance of FL SMN2mini mRNA is normalized to GAPDH mRNAabundance. The normalized FL SMN2mini mRNA abundance from testcompound-treated samples is then divided by normalized FL SMN2mini mRNAabundance from vehicle-treated cells to determine the level of FLSMN2mini mRNA relative to vehicle control.

Table 2 provides EC_(1.5×) concentrations for production of full lengthSMN2 minigene mRNA that was obtained from the 7-point concentration datagenerated according to the above procedure for particular compounds ofthe present invention.

Particular compounds of the present invention exhibit an EC_(1.5×)concentration for production of full length SMN2 minigene mRNA ≦1 μM.

More particular compounds of the present invention exhibit an EC_(1.5×)concentration for production of full length SMN2 minigene mRNA ≦0.1 μM.

Most particular compounds of the present invention exhibit anEC1.5×concentration for production of full length SMN2 minigene mRNA≦0.02 μM.

TABLE 2 EC_(1.5x) concentrations for production of full length SMN2minigene mRNA. Ex. EC_(1.5x) minigene (μM) 1 0.0316 2 0.1399 3 0.5522 40.2323 5 0.0612 6 0.2332 7 0.1423 8 0.201 9 0.794 10 0.6652 11 0.2971 120.3122 13 1.0335 14 0.2314 15 0.2539 16 1.0364 17 0.2334 18 0.0523 190.2673 20 0.4894 21 0.3856 22 0.2626 23 0.201 24 0.6489 25 0.3823 260.0445 27 0.0989 28 0.2524 29 0.2667 30 0.4096 31 0.1195 32 0.0938 33 340.328 35 0.2022 36 0.0278 37 0.028 38 0.4717 39 0.0168 40 0.0108 41 420.0544 43 0.057 44 0.0648 45 0.0615 46 0.0887 47 0.3964 48 0.0164 490.0107 50 0.0068 51 0.0084 52 0.04 53 0.2104 54 0.0128 55 0.1411 560.017 57 0.0262 58 0.0398 59 0.1089 60 0.0428 61 0.01 62 0.0136 630.1602 64 0.0291 65 0.0762 66 0.5177 67 0.3175 68 0.0285 69 0.0308 70 710.077 72 0.015 73 0.062 74 0.0161 75 0.0654 76 0.0187 77 0.0641 780.6222 79 0.0559 80 0.1148 81 0.0374 82 0.3714

Example D.2 SMN Protein Assay in Cultured Cells

The SMN HTRF (homogeneous time resolved fluorescence) assay is used toquantify the level of SMN protein in SMA patient fibroblast cellstreated with test compounds.

Material Source SMA Type 1 human GM03813 (Coriell Institute) cellsProtease inhibitor Roche Applied Science Catalog No. cocktail11836145001 Anti-SMN d2 Blue cap Cisbio Catalog No. 63IDC002-SMNAnti-SMN kryptate Red cap Cisbio Catalog No. 63IDC002-SMN SMNreconstitution Cisbio Catalog No. 63IDC002-SMN-Buffer buffer DMEM LifeTechnologies (formerly Invitrogen) Catalog No. 11960-044 RIPA LysisBuffer 20 mM Tris-HCl pH 7.5, 150 mM NaCl, 1 mM EDTA, 1% ThermoScientific NP-40 Surfact- Amps Detergent Solution (Fisher Scientific,Pittsburgh/PA), 1% Sodium deoxycholate Diluent Buffer 20 mM Tris-HCl pH7.5, 150 mM NaCl Envision Plate Perkin Elmer Model # 2103 Reader

Cells are thawed and cultured in DMEM-10% FBS for 72 hours. Cells aretrypsinized, counted and re-suspended to a concentration of 25,000cells/mL in DMEM-10% FBS. The cell suspensions are plated at 5,000 cellsper well in a 96 well microtiter plate and incubated for 3 to hours.Test compounds are serially diluted 3.16-fold in 100% DMSO to generate a7-point concentration curve. 1 μL of test compound solution istransferred to cell-containing wells and cells are incubated for 48hours in a cell culture incubator (37° C., 5% C0₂, 100% relativehumidity). Triplicate samples are set up for each test compoundconcentration. After 48 hours, the supernatant is removed from the wellsand 25 μL of the RIPA lysis buffer, containing protease inhibitors, isadded to the wells and incubated with shaking at room temperature for 1hour. 25 μL of the diluent is added and then 35 μL of the resultinglysate is transferred to a 384-well plate, where each well contains 5 μLof the antibody solution (1:100 dilution of anti-SMN d2 and anti-SMNkryptate in SMN reconstitution buffer). The plate is centrifuged for 1minute to bring the solution to the bottom of the wells, then incubatedovernight at room temperature. Fluorescence for each well of the plateat 665 nm and 620 nm is measured on an EnVision multilabel plate reader(Perkin-Elmer).

The normalized fluorescence signal is calculated for each sample, Blankand vehicle control well by dividing the signal at 665 nm by the signalat 620 nm. Normalizing the signal accounts for possible fluorescencequenching due to the matrix effect of the lysate. The ΔF value (ameasurement of SMN protein abundance as a percent value) for each samplewell is calculated by subtracting the normalized average fluorescencefor the Blank control wells from the normalized fluorescence for eachsample well, then dividing this difference by the normalized averagefluorescence for the Blank control wells and multiplying the resultingvalue by 100. The ΔF value for each sample well represents the SMNprotein abundance from test compound-treated samples. The ΔF value foreach sample well is divided by the ΔF value for the vehicle controlwells to calculate the fold increase in SMN protein abundance relativeto the vehicle control. Table 3 provides EC_(1.5×)concentrations for SMNprotein expression that was obtained from the 7-point concentration datagenerated according to the above procedure for particular compounds ofthe present invention.

Particular compounds of the present invention exhibit an EC_(1.5×)concentration for SMN protein expression ≦2 μM.

More particular compounds of the present invention exhibit an EC_(1.5×)concentration for SMN protein expression ≦0.3 μM.

Most particular compounds of the present invention exhibit an EC_(1.5×)concentration for SMN protein expression ≦0.1 μM.

Table 4 provides the maximum fold increase of SMN protein that wasobtained from the 7-point concentration data generated according to theabove procedure for particular compounds of the present invention

Particular compounds of the present invention exhibit a maximum foldincrease >1.4.

More particular compounds of the present invention exhibit a maximumfold increase >1.7.

Most particular compounds of the present invention exhibit a maximumfold increase >1.8.

TABLE 3 EC_(1.5x) concentrations for SMN protein expression. Ex.EC_(1.5x) SMN protein (μM) 1 0.7747 2 0.2984 3 1.47 4 0.5614 5 0.107 60.5305 7 0.2834 8 0.5175 9 1.527 10 0.329 11 0.321 12 0.7037 13 1.756414 0.7944 15 0.281 16 1.1992 17 0.5022 18 0.1346 19 1.3818 20 0.8065 210.6542 22 0.4468 23 0.5092 24 1.2616 25 0.5694 26 0.2853 27 0.3964 280.2868 29 0.4618 30 0.7612 31 0.2746 32 0.2028 33 0.5703 34 0.7793 351.2664 36 0.1094 37 0.1196 38 0.6124 39 0.0147 40 0.0276 41 0.0508 420.1488 43 0.104 44 0.13 45 0.5147 46 0.3584 47 0.611 48 0.0621 49 0.173350 0.0344 51 0.0561 52 0.1518 53 0.7455 54 0.056 55 0.7112 56 0.07 571.7363 58 0.1159 59 0.2749 60 0.107 61 62 63 1.0431 64 0.1192 65 0.113566 0.6108 67 0.866 68 0.057 69 0.1645 70 0.0187 71 0.4077 72 0.1324 730.7589 74 0.1524 75 0.3061 76 0.1629 77 0.2279 78 1.013 79 0.2559 800.52 81 0.2723 82 0.7698

TABLE 4 Maximum fold increase of SMN protein. Ex. max. fold increase 11.6736 2 1.8878 3 1.7558 4 1.769 5 1.7757 6 1.8047 7 1.7936 8 1.7677 91.6085 10 1.735 11 1.7143 12 1.6512 13 1.624 14 1.5912 15 1.6859 161.6598 17 1.6966 18 1.7677 19 1.664 20 1.7789 21 1.7755 22 1.7566 231.6942 24 1.756 25 1.6652 26 1.8316 27 1.6617 28 1.7291 29 1.632 301.6734 31 1.7849 32 1.7579 33 1.7541 34 1.6527 35 1.6275 36 1.7018 371.7758 38 1.8706 39 1.8791 40 1.7607 41 1.7973 42 1.6988 43 1.7873 441.8243 45 1.6445 46 1.5572 47 1.7065 48 1.738 49 1.658 50 1.6607 511.7266 52 1.8152 53 1.6563 54 1.8217 55 1.8752 56 1.7299 57 1.578 581.7744 59 1.7116 60 1.7375 61 1.7077 62 1.5583 63 1.6807 64 1.7581 651.7675 66 1.5438 67 1.6552 68 1.6943 69 1.7612 70 1.933 71 1.4815 721.7095 73 1.5775 74 1.709 75 1.7035 76 1.7274 77 1.6649 78 1.7897 791.6574 80 1.5928 81 1.6719 82 1.7306

1. A compound of formula (I):

wherein: X is N or CR³; Y is N or CR⁴; with the proviso that not both Xand Y are N; A is a bicyclic 9-membered heteroaryl comprising two orthree heteroatoms independently selected from N or O, wherein A can beoptionally substituted with one, two or three R⁵; B is a saturated orpartially unsaturated mono- or bicyclic 4 to 9-membered heterocycloalkylcomprising one or two ring nitrogen atoms, the remaining ring atomsbeing carbon, wherein B can be optionally substituted with one, two orthree R⁶; R¹ is hydrogen, halo, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₁₋₇-alkoxyor C₁₋₇-haloalkoxy; R² is hydrogen, halo, C₁₋₇-alkyl, C₁₋₇-haloalkyl,C₁₋₇-alkoxy or C₁₋₇-haloalkoxy; R³ is hydrogen, halo, C₁₋₇-alkyl,C₁₋₇-haloalkyl, C₁₋₇-alkoxy or C₁₋₇-haloalkoxy; R⁴ is hydrogen, halo,C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₁₋₇-alkoxy or C₁₋₇-haloalkoxy; each R⁵ isindependently selected from halo, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl orC₃₋₇-cycloalkyl; each R⁶ is independently selected from C₁₋₇-alkyl, ortwo R⁶ together form a C₂₋₇-alkylene; or a pharmaceutically acceptablesalt thereof.
 2. The compound according to claim 1, wherein A isselected from the group of imidazo[1,2-a]pyrazin-2-yl,imidazo[1,2-a]pyridinyl, and benzo[d]oxazolyl, which can be optionallysubstituted with one, two or three R⁵.
 3. The compound according toclaim 1, wherein A is selected from the group ofimidazo[1,2-a]pyrazin-2-yl substituted with two C₁₋₇-alkyl,imidazo[1,2-a]pyridin-6-yl substituted with one or two C₁₋₇-alkyl,imidazo[1,2-a]pyridin-6-yl substituted with one C₁₋₇-alkyl and one halo,imidazo[1,2-a]pyridin-6-yl substituted with one C₁₋₇-alkyl and oneC₁₋₇-haloalkyl, benzo[d]oxazol-6-yl substituted with one C₁₋₇-alkyl, andbenzo[d]oxazol-6-yl substituted with one C₁₋₇-alkyl and one halo.
 4. Thecompound according to claim 1, wherein A is selected from2-methylbenzo[d]oxazol-6-yl, 4-fluoro-2-methylbenzo[d]oxazol-6-yl,6,8-dimethylimidazo[1,2-a]pyrazin-2-yl,2-methylimidazo[1,2-a]pyridin-6-yl,2,7-dimethylimidazo[1,2-a]pyridin-6-yl,2,8-dimethylimidazo[1,2-a]pyridin-6-yl,2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl,8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl, and8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl.
 5. The compound accordingto claim 1, wherein each R⁵ is independently selected from halo,C₁₋₇-alkyl, or C₁₋₇-haloalkyl.
 6. The compound according to any claim 1,wherein each R⁵ is independently selected from methyl, fluoro, chloro,and trifluoromethyl.
 7. The compound according to claim 1, wherein B asdefined herein is further characterized in that one ring nitrogen atomsis basic.
 8. The compound according to claim 1, wherein B is selectedfrom 1,2,3,6-tetrahydropyridinyl, 2,6-diazaspiro[3.3]heptanyl,hexahydropyrrolo[3,4-c]pyrrolyl, hexahydropyrrolo[1,2-a]pyrazinyl,piperazinyl, and piperidinyl, wherein each can be optionally substitutedwith one, two or three R⁶.
 9. The compound according to claim 1, whereinB is selected from piperazin-1-yl, 3-methyl-piperazin-1-yl, and3,3-dimethylpiperazin-1-yl.
 10. The compound according to claim 1,wherein each R⁶ is C₁₋₇-alkyl.
 11. The compound according to claim 1,wherein each R⁶ is independently selected from methyl, and ethyl. 12.The compound according to claim 1, wherein X is CR³ and Y is CR⁴, or Xis N and Y is CR⁴, or X is CR³ and Y is N.
 13. The compound according toclaim 1, wherein X is CR³ and Y is CR⁴.
 14. The compound according toclaim 1, wherein X is N and Y is CR⁴.
 15. The compound according toclaim 1, wherein R¹ is hydrogen, halo, C₁₋₇-alkoxy or C₁₋₇-haloalkoxy.16. The compound according to claim 1, wherein R¹ is hydrogen, fluoro,methoxy, ethoxy or trifluoroethoxy.
 17. The compound according to claim1, wherein R¹ is hydrogen.
 18. The compound according to claim 1,wherein R² is hydrogen, halo, or C₁₋₇-alkyl.
 19. The compound accordingto claim 1, wherein R² is hydrogen, fluoro or methyl.
 20. The compoundaccording to claim 1, wherein R² is hydrogen.
 21. The compound accordingto claim 1, wherein R³ is hydrogen or fluoro.
 22. The compound accordingto claim 1, wherein R³ is hydrogen.
 23. The compound according to claim1, wherein R⁴ is hydrogen, halo or C₁₋₇-alkoxy.
 24. The compoundaccording to claim 1, wherein R⁴ is hydrogen, fluoro, methoxy, ethoxy ortrifluoroethoxy.
 25. The compound according to claim 1, wherein R⁴ ishydrogen or fluoro.
 26. The compound according to claim 1, wherein R⁴ ishydrogen, halo or C₁₋₇-alkoxy.
 27. The compound according to claim 1,selected from the group consisting of:N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(piperazin-1-yl)benzamide;rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(3-methylpiperazin-1-yl)benzamide;N-(6,8-Dimethyl-imidazo[1,2-a]pyrazin-2-yl)-4-((S)-3-methyl-piperazin-1-yl)-benzamide;N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(4-methylpiperazin-1-yl)benzamide;rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide;N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-methylpiperazin-1-yl)nicotinamide;rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-ethylpiperazin-1-yl)nicotinamide;N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(4-methylpiperazin-1-yl)picolinamide;rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(3-methylpiperazin-1-yl)picolinamide;N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(piperazin-1-yl)picolinamide;rac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;6-(3,3-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nicotinamide;N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;6-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nicotinamide;N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(2,6-diazaspiro[3.3]heptan-2-yl)nicotinamide;rac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin-1-yl)picolinamide;rac-2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide:rac-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;(S)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)nicotinamide;6-(3,5-dimethylpiperazin-1-yl)-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)nicotinamide;6-(3,5-dimethylpiperazin-1-yl)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)nicotinamide;N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-6-(4-methylpiperazin-1-yl)nicotinamide;(S)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinamide;N-(4-Fluoro-2-methyl-benzooxazol-6-yl)-6-piperazin-1-yl-nicotinamide;rac-N-(4-Fluoro-2-methyl-benzooxazol-6-yl)-6-(3-methyl-piperazin-1-yl)-nicotinamide;N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)benzamide;rac-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;4-(3,5-dimethylpiperazin-1-yl)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)benzamide;(S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)benzamide;N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(4-methylpiperazin-1-yl)nicotinamide;(S)-2-Fluoro-N-(4-fluoro-2-methyl-benzooxazol-6-yl)-4-(S)-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl-benzamide;(R)-2-fluoro-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzamide;(S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)benzamide;N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzamide;rac-N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide;rac-2-fluoro-N-(2-methylbenzo[d]oxazol-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;rac-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzamide;N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin-1-yl)picolinamide;2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzamide;rac-2,3-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;rac-2,5-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;rac-5-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;rac-3-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin-1-yl)picolinamide;rac-2,6-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;(S)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;(R)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;rac-N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide;rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-6-(3-methylpiperazin-1-yl)nicotinamide;rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide;rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nicotinamide;rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-fluoro-5-(3-methylpiperazin-1-yl)picolinamide;rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2,6-difluoro-4-(3-methylpiperazin-1-yl)benzamide;2-fluoro-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)benzamide;2-fluoro-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzamide;2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide;2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide;N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)nicotinamide;N-(2-methylimidazo[1,2-a]pyridin-6-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)picolinamide;N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(piperazin-1-yl)nicotinamide;2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-methyl-4-(piperazin-1-yl)benzamide;N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-methyl-6-(piperazin-1-yl)nicotinamide;4-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(piperazin-1-yl)nicotinamide;4-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)-4-(2,2,2-trifluoroethoxy)nicotinamide;2-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)-2-(2,2,2-trifluoroethoxy)nicotinamide;rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(3-methylpiperazin-1-yl)nicotinamide;6-(3,3-dimethylpiperazin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxynicotinamide;rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(3-methylpiperazin-1-yl)nicotinamide;N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)nicotinamide;N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl)nicotinamide;N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperidin-4-yl)nicotinamide;N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl)nicotinamide;2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperidin-4-yl)benzamide;andrac-6-(3,4-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nicotinamide;or a pharmaceutically acceptable salt thereof.
 28. The compoundaccording to claim 1, selected from the group consisting of:rac-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzamide;N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;rac-3-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin-1-yl)picolinamide;rac-2,6-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;(S)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;(R)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide;rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide;rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-fluoro-5-(3-methylpiperazin-1-yl)picolinamide;2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide;N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)nicotinamide;4-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;4-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;2-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(3-methylpiperazin-1-yl)nicotinamide;andrac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(3-methylpiperazin-1-yl)nicotinamide;or a pharmaceutically acceptable salt thereof.
 29. A process for thepreparation of a compound according to claim 1, comprising the step of:a) the Buchwald-Hartwig amination reaction of a compound of formula (II)

with a compound of formula B—H, in the presence of a catalyst and aligand and a base and a solvent, wherein the hydrogen H of the compoundof formula B—H is bound to a ring nitrogen atom of B, V is chloro orbromo, and A, B, X, Y, R¹, and R² are as defined in claim 1; or b) anucleophilic aromatic substitution reaction between a compound offormula (II) with a compound of formula B—H by heating in a solvent,wherein the hydrogen H of the compound of formula B—H is bound to a ringnitrogen atom of B, V is fluoro if X is CR³ or V is chloro if X is N,and A, B, X, Y, R¹, R² and R³ are as defined in claim 1; or c) theSuzuki coupling reaction of a compound of formula (II) with a compoundof formula PG-B-pinB in the presence of a base and a catalyst, followedby removal of PG, wherein pinB is pinacolboranyl which is bound to aring carbon atom of B, PG is an amino-protecting group, V is fluoro orchloro, and wherein A, B, X, Y, R¹, and R² are as defined in claim 1; ord) the amidation reaction of a compound of formula (III)

with a compound of formula A-NH₂ in the presence of a tertiary amine anda coupling reagent, optionally followed by the removal of PG, wherein PGis an optional amino-protecting group, and wherein A, B, X, Y, R¹, andR² are as defined in claim
 1. 30. (canceled)
 31. A pharmaceuticalcomposition, comprising a therapeutically effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof, andone or more pharmaceutically acceptable excipients. 32-33. (canceled)34. A method for the treatment or prevention of spinal muscular atrophy(SMA), comprising the step of administering a therapeutically effectiveamount of a compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, to a subject in need thereof. 35-37. (canceled)